Substituted isoquinolines and isoquinolinones as rho kinase inhibitors

ABSTRACT

The invention relates to substituted isoquinoline and isoquinolinones of the formula (I) useful for the treatment and/or prevention of diseases associated with Rho-kinase and/or Rho-kinase mediated phosphorylation of myosin light chain phosphatase, and compositions containing such compounds.

The present invention relates to substituted isoquinoline andisoquinolinones, their preparation and their use in the treatment and/orprevention of diseases related to the inhibition of Rho-kinase and/or ofRho-kinase mediated phosphorylation of myosin light chain phosphatase.

Activation of a small GTPase RhoA upon agonist stimulation results inconversion of RhoA from the inactive GDP-bound form to the activeGTP-bound form with a subsequent binding to and activation ofRho-kinase. Two isoforms, Rho-kinase 1 and Rho-kinase 2, are known.Rho-kinase 2 is expressed in vascular smooth muscle cells andendothelial cells. Activation of Rho-kinase 2 by the active GTP-boundRhoA leads to calcium sensitization of smooth muscle cells throughphosphorylation-mediated inhibition of the myosin light chainphosphatase activity and thereby up-regulation of the activity of myosinregulatory light chain (Uehata et al., Nature 1997, 389, 990-994).

It is known that Rho-kinase is involved in vasoconstriction, includingthe development of myogenic tone and smooth muscle hypercontractility(Gokina et al. J. Appl. Physiol. 2005, 98, 1940-1948), bronchial smoothmuscle contraction (Yoshii et al. Am. J. Resp. Cell Mol. Biol. 1999, 20,1190-1200), asthma (Setoguchi et al. Br. J. Pharmacol. 2001, 132,111-118; Nakahara et al. Eur. J. Pharmac. 2000, 389, 103-106) andchronic obstructive pulmonary disease (COPD, Maruoka et al. NipponRinsho, 1999, 57, 1982-1987), hypertension, pulmonary hypertension(Fukumoto et al. Heart 2005, 91, 391-392, Mukai et al. Nature 1997, 389,990-994) and ocular hypertension and regulation of intraoccular pressure(Honjo et al. Invest. Ophthalmol. Visual Sci. 2001, 42, 137-144),endothelial dysfunction (Steioff et al. Eur. J. Pharmacol. 2005, 512,247-249), angina (Masumoto et al. Circulation 2002, 105, 1545-47,Shimokawa et al. J. Cardiovasc. Pharmacol. 2002, 40, 751-761),nephropathy, including hypertension-induced, non-hypertension-induced,and diabetic nephropathies, renal failure and peripheral arterialocclusive disease (PAOD) (Wakino et al. Drug News Perspect. 2005, 18,639-643), myocardial infarction (Demiryurek et al. Eur. J. Pharmacol.2005, 527, 129-140, Hattori et al. Circulation 2004, 109, 2234-2239),cardiac hypertrophy and failure (Yamakawa et al. Hypertension 2000, 35,313-318; Liao et al. Am. J. Physiol. Cell Physiol. 2006, 290, C661-668;Kishi et al. Circulation 2005, 111, 2741-2747), coronary heart disease,artherosclerosis, restenosis (Pacaud et al. Arch. Mal. Coeur 2005, 98,249-254; Retzer et al. FEBS Lett. 2000, 466, 70-74; Negoro et al.Biochem. Biophys. Res. Commun. 1999, 262, 211-215), diabetes, diabeticcomplications, glucose utilization and metabolic syndrome (Sandu et al.Diabetes 2000, 49, 2178-2189; Maeda et al. Cell Metab. 2005, 2,119-129), sexual dysfunction, e.g., penile erectile dysfunction(Chitaley et al. Nature Medicine 2001, 7, 119-122), retinopathy,inflammation, immune diseases, AIDS, osteoporosis, endocrinedysfunctions, e.g. hyperaldosteronism, central nervous system disorderssuch as neuronal degeneration and spinal cord injury (Hara et al. J.Neurosurg. 2000, 93, 94-101), cerebral ischemia (Uehara et al. Nature1997, 389, 990-994; Satoh et al. Life Sci. 2001, 69, 1441-1453; Hitomiet al. Life Sci. 2000, 67, 1929-1939; Yamamoto et al. J. Cardiovasc.Pharmacol. 2000, 35, 203-211), cerebral vasospasm (Sato et al. Circ.Res. 2000, 87, 195-200; Kim et al. Neurosurgery 2000, 46, 440-447),pain, e.g. neuropathic pain (Tatsumi et al. Neuroscience 2005, 131,491-498; Inoue et al. Nature medicine 2004, 10, 712-718), infection ofdigestive tracts with bacteria (WO 98/06433), cancer development andprogression, neoplasia where inhibition of Rho kinase has been shown toinhibit tumor cell growth and metastasis (Itoh et al. Nature Medicine1999, 5, 221-225; Somlyo et al. Biochem. Biophys. Res. Commun. 2000,269, 652-659), angiogenesis (Uchida et al. Biochem. Biophys. Res.Commun. 2000, 269, 633-640; Gingras et al. Biochem. J. 2000, 348,273-280), vascular smooth muscle cell proliferation and motility (Tammyet al. Circ. Res. 1999, 84, 1186-1193; Tangkijvanich et al.Atherosclerosis 2001, 155, 321-327), endothelial cell proliferation,endothelial cell retraction and motility (Oikawa et al. Biochem.Biophys. Res. Commun. 2000, 269, 633-640), stress fiber formation(Kimura et al. Science 1997, 275, 1308-1311; Yamashiro et al. J. CellBiol. 2000, 150, 797-806), thrombotic disorders (Kikkawa et al. FEBSLett. 2000, 466, 70-74; Bauer et al. Blood 1999, 94, 1665-1672; Klageset al. J. Cell Biol. 1999, 144, 745-754; Retzer et al. Cell Signal 2000,12, 645-648) and leukocyte aggregation (Kawaguchi et al. Eur. J.Pharmacol. 2000, 403, 203-208; Sanchez-Madrid et al. J. Immunol. 2003,171, 1023-1034; Sanchez-Madrid, et al. J. Immunol. 2002, 168, 400-410),stem cell and induced pluripotent stem cell related biology, e.g.cell-cell interaction, proliferation, cell cycle progression, generegulation, migration, actin cytoskeleton modulation, and relatedapplication, e.g. as viability, survival, recovery, growth,susceptibility toward apoptosis, differentiation, development, genemodulation, modulation of morphogenesis, hosting and invasion (Krawetzet al. BioEssay 2009, 31, 336-343; Claassen et al. Mol. Reprod. Dev.2009, PMID: 19235204; Heng Tissue Cell 2009, PMID: 19261317; Arnsdorf etal. J. Cell. Sci. 2009, 122, 546-553, Kim et al. Stem Cells 2009, 27,191-199), modulation of epithelial-mesenchymal transition (Royal et al.Mol. Biol. Cell 2000, 11, 1709-1725; Zondag et al. J. Cell Biol. 2000,149, 775-782; Masszi et al. Am. J. Physiol. Renal. Physiol. 2003, 284,911-924; Smallhorn et al. Development 2004, 131, 2641-2651; Wells et al.Cell Motil. Cytoskeleton 2005, 62, 180-194; Wu et al. Cancer Res. 2006,66, 9527-9534; Fan et al. Mol Biol Cell. 2007, 18, 1083-1097; Cho et al.Cell Biol. Int. 2007, 31, 1225-1230; Giehl et al. Cells Tissues Organs.2007, 185, 123-130; Rodrigues-Díez et al. Pharm. Res. 2008, 25,2447-2461), and bone resorption (Chellaiah et al. J. Biol. Chem. 2003,278, 29086-29097). Na/H exchange transport system activation (Kawaguchiet al. Eur. J. Pharmacol. 2000, 403, 203-208), Alzheimer's disease (Zhouet al. Science 2003, 302, 1215-1217), adducin activation (Fukata et al.J. Biol. Chem., 1998, 273, 5542-5548), and in SREB (Sterol responsebinding element) signalling and its effects on lipid metabolism (Lin etal. Circ. Res. 2003, 92, 1296-304).

Therefore, a compound having inhibitory effect on Rho-kinase and/or onRho-kinase mediated phosphorylation of myosin light chain phosphatase isuseful for the treatment and/or prevention of cardiovascular andnon-cardiovascular diseases involving Rho-kinase as the primary orsecondary disease cause, like hypertension, pulmonary hypertension,ocular hypertension, retinopathy, and glaucoma, peripheral circulatorydisorder, peripheral arterial occlusive disease (PAOD), coronary heartdisease, angina pectoris, heart hypertrophy, heart failure, ischemicdiseases, ischemic organ failure (end organ damage), fibroid lung,fibroid liver, liver failure, nephropathy, includinghypertension-induced, non-hypertension-induced, and diabeticnephropathies, renal failure, fibroid kidney, renal glomerulosclerosis,organ hypertrophy, asthma, chronic obstructive pulmonary disease (COPD),adult respiratory distress syndrome, thrombotic disorders, stroke,cerebral vasospasm, cerebral ischemia, pain, e.g. neuropathic pain,neuronal degeneration, spinal cord injury, Alzheimer's disease,premature birth, erectile dysfunction, endocrine dysfunctions,arteriosclerosis, prostatic hypertrophy, diabetes and complications ofdiabetes, metabolic syndrome, blood vessel restenosis, atherosclerosis,inflammation, autoimmune diseases, AIDS, osteopathy such asosteoporosis, infection of digestive tracts with bacteria, sepsis,cancer development and progression, e.g. cancers of the breast, colon,prostate, ovaries, brain and lung and their metastases.

Moreover, such a compound is also useful for curative approachesassociated with stem cell or induced pluripotent stem cell treatment,improvement of recognition or for treatment or prevention of depression,epilepsy, fibroid heart, renal papillary necrosis, tubulo-interstitialdysfunction, multiple sclerosis, vessel stenosis for example carotidstenosis or lipid disorders.

WO 2001/64238 describes isoquinoline-5-sulfonamide derivativesoptionally substituted by a —(CH₂)₁₋₆—O—(CH₂)₀₋₆—, a—(CH₂)₀₋₆—S—(CH₂)₀₋₆— or a —(CH₂)₀₋₆— linked heterocyclic group usefulas neuroprotective agents.

WO 2004/106325 (Schering A G) describes prodrugs of the Rho-kinaseinhibitor fasudil carrying an ether or ester group in the 1-position ofthe isoquinoline ring.

WO 2001/039726 generically describes —O—(C₀-C₁₀)alkyl-heteroarylsubstituted cyclohexyl derivatives useful for the treatment of microbialinfections.

JP 10087629 A describes isoquinoline derivatives useful for thetreatment of diseases caused by Heliobacter pylori such as for examplegastritis cancer or ulcer. The isoquinoline derivatives may besubstituted by OH in the 1-position and are preferably 5-substituted byX—[(C₁-C₆)alkylene)]₀₋₁-Y wherein X may be oxygen and Y may be an arylor a heterocyclic group.

Hagihara et al. (Bioorg. Med. Chem. 1999, 7, 2647-2666) disclose6-benzyloxy-isoquinoline for the treatment of infections caused byHeliobacter pylori.

U.S. Pat. No. 5,480,883 generically discloses as EGF and/or PDGFreceptor inhibitors useful for inhibiting cell proliferation compoundsof the formula “Ar I—X—Ar II” wherein X may be (CHR₁)_(m)—Z—(CHR₁)_(n),e.g. Z—CH₂, wherein Z may be O, R₁ is hydrogen or alkyl, Ar I may beamong others an optionally substituted isoquinolone and Ar II may beamong others an optionally substituted C₃₋₇ monocyclic saturatedheterocyclic system.

WO 2005/030791 (Merck & Co.) generically describes as potassium channelinhibitors for the treatment of cardiac arrhythmias, stroke, congestiveheart failure etc. isoquinolone derivatives which are optionallysubstituted in 6-position by a group (CR^(e)R^(f))_(p)OR⁴³ wherein p maybe zero, and R⁴³ is e.g. a (C₃-C₁₀)cycloalkyl residue optionallysubstituted by NR⁵¹R⁵², wherein R⁵¹ and R⁵² may be hydrogen,(C₁-C₆)alkyl etc.; or R⁴³ is a group R⁸¹ defined as a 4-6 memberedunsaturated or saturated monocyclic heterocylic ring with 1, 2, 3 or 4heteroatoms; and are substituted by a directly bound optionallysubstituted aryl or heteroaryl ring in the 4-position.

WO 2005/030130 (Merck & Co.) generically describes as potassium channelinhibitors for the treatment of cardiac arrhythmias, stroke, congestiveheart failure etc. isoquinoline derivatives which may be substituted byhydroxy in the 1-position and are optionally substituted in 6-positionby a group (CR^(e)R^(f))_(p)OR⁴³ wherein p may be zero, and R⁴³ is e.g.a (C₃-C₁₀)cycloalkyl residue optionally substituted by NR⁵¹R⁵², whereinR⁵¹ and R⁵² may be hydrogen, (C₁-C₆)alkyl etc.; or R⁴³ is a group R⁸¹defined as a 4-6 membered unsaturated or saturated monocyclicheterocylic ring with 1, 2, 3 or 4 heteroatoms; and are substituted by adirectly bound optionally substituted aryl or heteroaryl ring in the4-position.

WO2003/053330 (Ube) generically describes isoquinolone derivatives ofthe formula

as Rho-kinase inhibitors.

WO 2007/012422 (Sanofi-Aventis) generically describes isoquinoline andisoquinolone derivatives of the formula

as Rho-Kinase inhibitors.

WO2008/077556 (Sanofi-Aventis) describes further 6-substitutedisoquinoline and isoquinolone derivatives as Rho-Kinase inhibitors.

WO 2008/020081 (Organon) describes 6-substituted isoquinoline-1-one orisoquinoline 1-amine derivatives as Rho-kinase inhibitors.

Iwakubo et. al. (Bioorganic & Med. Chemistry Vol. 15, No. 1, 15.November 2006, p. 350-364) describe a 5-substituted isoquinoline andindazol derived derivatives as Rho-kinase inhibitors.

In particular selectivity against other kinases has been identified asprerequisite for usage of kinase inhibitors as therapeutic agents.Fasudil for instance, a broadly profiled inhibitor of Rho kinasedisplays only modest selectivity against several other kinases, forexample Protein Kinase A and Protein Kinase G (see for example Tamura etal., Biochimica et Biophysica Acta, Proteins and Proteomics (2005),1754(1-2), 245-252. Also another inhibitor, Y-27632 only displays a20-fold selectivity against Protein Kinase G.

Therefore, although several Rho-kinase inhibitors have been describedthere still remains the need for additional compounds useful in thetreatment of Rho-kinase mediated diseases, in particular with improvedselectivity.

An embodiment of the present invention is a compound of the formula (I)

wherein

R₁ is H, OH or NH₂;

R₃ is H, halogen, CN, (C₁-C₆)alkyl, OH, NH₂, or NHR′;R₄ is H, halogen, hydroxy, CN, (C₁-C₆)alkyl, R′, or (C₁-C₆)alkylene-R′;R₅ is H, halogen, CN, (C₁-C₆)alkyl, or R′;R₇ is H, halogen, CN, (C₁-C₆)alkyl, O—(C₁-C₆)alkyl, R′, or SO₂—NH₂;R₈ is H, halogen or (C₁-C₆)alkyl;

R₉ is R′, OH,

halogen,(C₁-C₆)alkyl,O—(C₁-C₆)alkyl,(C₁-C₆)alkylene-R′,(C₂-C₆)alkenyl,(C₂-C₆)alkynyl,(C₁-C₆)alkylene-O—R′,(C₁-C₆)alkylene-CH[R′]₂,(C₁-C₆)alkylene-C(O)—R′,(C₁-C₆)alkylene-C(O)NH₂,(C₁-C₆)alkylene-C(O)NH—R′,(C₁-C₆)alkylene-C(O)NH—(C₁-C₆)alkyl,(C₁-C₆)alkylene-C(O)N[(C₁-C₆)alkyl]₂,(C₁-C₆)alkylene-C(O)N[R′]₂;(C₁-C₆)alkylene-C(O)O—(C₁-C₆)alkyl,

COOH,

C(O)O—(C₁-C₆)alkyl,

C(O)OR′

C(O)(C₁-C₆)alkyl,

C(O)R′, C(O)NH₂,

C(O)—NH—(C₂-C₆)alkenyl,C(O)—NH—(C₂-C₆)alkynyl,C(O)NH—(C₁-C₆)alkyl,

C(O)NHR′,

C(O)—NH(C₁-C₆)alkylene-R′,C(O)N[(C₁-C₆)alkyl]R′C(O)N[(C₁-C₆)alkyl]₂,C(O)—(C₁-C₆)alkylene-R′, orC(O)O(C₁-C₆)alkylene-R′;R₆ is absent;or is one (C₁-C₄)alkylene bound to the cycloalkyl ring, in which the(C₁-C₄)alkylene forms a second bond to a different carbon atom of thecycloalkyl ring to form a bicyclic ring system,wherein in the bicyclic ring system optionally one or two carbon atomesare replaced by a group independently selected from O, N—R₁₅, S, SO orSO₂;or, if m and s are 2, m is 3 and s is 1, or m is 4 and s is 0,R₆ is CH₂—CH—(CH₂)₂ which is bound with one CH₂ to the cycloalkyl ringand the two other CH₂ are bound to different carbon atoms of thecycloalkyl ring;and, if m is 3 and s is 3,R₆ are two methylene groups bound to different carbon atoms of thecycloalkyl ring, wherein the methylene groups or the CH₂—CH—(CH₂)₂ groupare bound to carbon atoms of the cycloaalkyl ring such that they form anadamantane system of the formula

wherein L can be bound to any secondary or tertiary carbon atom andwherein the bicyclic ring system or adamantane system is unsubstitutedor optionally substituted by R₉.

R₁₀ is H,

(C₆-C₁₀)aryl,O—(C₆-C₁₀)aryl,O—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, or(C₆-C₁₀)heteroaryl, wherein (C₆-C₁₀)aryl or (C₆-C₁₀)heteroaryl areunsubstituted or substituted.

R₁₁ is H,

(C₁-C₆)alkyl,(C₁-C₆)alkylene-R′,(C₃-C₈)cycloalkyl,(C₅-C₁₀)heteroaryl,(C₃-C₈)heterocycloalkyl,(C₆-C₁₀)aryl;or R₁₁ and R₁₂ together with carbon atom to which they are attached forma (C₃-C₈)cycloalkyl or a (C₃-C₈)-heterocycloalkyl ring;

R₁₂ is

(C₁-C₆)alkyl,(C₃-C₅)cycloalkyl,(C₅-C₁₀)heteroaryl,(C₃-C₈)heterocycloalkyl, or(C₆-C₁₀)aryl;or R₁₂ is H, provided that r=2 and the other R₁₂ is not H;or R₁₁ and R₁₂ together with carbon atom to which they are attached forma (C₃-C₈)cycloalkyl or a (C₃-C₈)-heterocycloalkyl ring;R₁₃ and R₁₄ are independently of each other

H, R′,

(C₁-C₆)alkyl,(C₁-C₆)alkylene-R′,(C₁-C₆)alkylene-O—(C₁-C₆)alkyl,(C₁-C₆)alkylene-O—R′,(C₁-C₆)alkylene-CH[R′]₂,(C₁-C₆)alkylene-C(O)—R′,(C₁-C₆)alkylene-C(O)NH₂,(C₁-C₆)alkylene-C(O)NH—R′,(C₁-C₆)alkylene-C(O)NH—(C₁-C₆)alkyl,(C₁-C₆)alkylene-C(O)N[(C₁-C₆)alkyl]₂,(C₁-C₆)alkylene-C(O)N[R′]₂,(C₁-C₆)alkylene-C(O)O—(C₁-C₆)alkyl,C(O)O—(C₁-C₆)alkyl,

C(O)OR′,

C(O)(C₁-C₆)alkyl,

C(O)R′,

C(O)NH—(C₁-C₆)alkyl,

C(O)NHR′,

—C(O)N[(C₁-C₆)alkyl],C(O)N[(C₁-C₆)alkyl]₂,C(O)—(C₁-C₆)alkylene-R′,C(O)O(C₁-C₆)alkylene-R′, orR₁₃ and R₁₄, together with the N-atom to which they are attached, form a(C₃-C₈) heterocycloalkyl;R₁₅ is H or (C₁-C₆)alkyl;n is 0, 1, 2, 3 or 4;m is 1, 2, 3 or 4;s is 0, 1, 2, or 3;r is 1 or 2;L is O(CH₂)_(p), S(CH₂)_(p), S(O)(CH₂)_(p), SO₂(CH₂)_(p), NH(CH₂)_(p),N(C₁-C₆)alkyl-(CH₂)_(p), N(C₃-C₆)cycloalkyl-(CH₂)_(p); orN[(C₁-C₃)alkylene-R′]—(CH₂)_(p);p is 0, 1, 2, 3 or 4;

R′ is

(C₃-C₈)cycloalkyl,(C₅-C₁₀)heteroaryl,(C₃-C₈)heterocycloalkyl,(C₆-C₁₀)aryl;wherein in residues R₃ to R₁₅ alkyl or alkylene is unsubstituted oroptionally substituted one or more times by OH, OCH₃, C(O)OH, C(O)OCH₃,NH₂, NHCH₃, N(CH₃)₂, C(O)NH₂, C(O)NHCH₃ or C(O)N(CH₃)₂;wherein in residues R₃ to R₁₅ cycloalkyl or heterocycloalkyl isunsubstituted or optionally substituted one or more times by(C₁-C₆)alkyl, halogen, OH, OCH₃, C(O)OH, C(O)OCH₃, NH₂, NHCH₃, N(CH₃)₂,C(O)NH₂, C(O)NHCH₃ or C(O)N(CH₃)₂;wherein in residues R₃ to R₁₅ alkyl or alkylene is unsubstituted oroptionally substituted one or more times by halogen;wherein in residues R₃ to R₁₅ (C₆-C₁₀)aryl and (C₅-C₁₀)heteroaryl areunsubstituted or optionally substituted one or more times by a groupindependently selected from halogen, OH, NO₂, N₃, CN, C(O)—(C₁-C₆)alkyl,C(O)—(C₆-C₁₀)aryl, COOH, COO(C₁-C₆)alkyl, CONH₂, CONH(C₁-C₆)alkyl,CON[(C₁-C₆)alkyl]₂, (C₃-C₈)cycloalkyl, (C₁-C₆)alkyl,(C₁-C₆)alkylene-NH(C₁-C₆)alkyl, (C₁-C₆)alkylene-N[(C₁-C₆)alkyl]₂,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, O—(C₁-C₆)alkyl, O—C(O)—(C₁-C₆)alkyl,PO₃H₂, SO₃H, SO₂—NH₂, SO₂NH(C₁-C₆)alkyl, SO₂N[(C₁-C₆)alkyl]₂,S—(C₁-C₆)alkyl; SO—(C₁-C₆)alkyl, SO₂—(C₁-C₆)alkyl,SO₂—N═CH—N[(C₁-C₆)alkyl]₂, SF₅, C(NH)(NH₂), NH₂, NH—(C₁-C₆)alkyl,N[(C₁-C₆)alkyl]₂, NH—C(O)—(C₁-C₆)alkyl, NH—C(O)O—(C₁-C₆)alkyl,NH—SO₂—(C₁-C₆)alkyl, NH—SO₂—(C₆-C₁₀)aryl, NH—SO₂—(C₅-C₁₀heteroaryl,NH—SO₂—(C₃-C₈)heterocycloalkyl, N(C₁-C₆)alkyl-C(O)—(C₁-C₆)alkyl,N(C₁-C₆)alkyl-C(O)O—(C₁-C₆)alkyl, N(C₁-C₆)alkyl-C(O)—NH—(C₁-C₆)alkyl],(C₆-C₁₀)aryl, (C₁-C₆)alkylene-(C₆-C₁₀)aryl, O—(C₆-C₁₀)aryl,O—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, (C₅-C₁₀)heteroaryl,(C₃-C₈)heterocycloalkyl, (C₁-C₆)alkylene-(C₅-C₁₀)heteroaryl,(C₁-C₆)alkylene-(C₃-C₈)heterocycloalkyl,O—(C₁-C₆)alkylene-(C₅-C₁₀)heteroaryl,O—(C₁-C₆)alkylene-(C₃-C₈)heterocycloalkyl, wherein said (C₆-C₁₀)aryl,(C₅-C₁₀)heteroaryl, (C₃-C₈)heterocycloalkyl or (C₃-C₈)cycloalkyl may besubstituted one to three times by a group independently selected fromhalogen, OH, NO₂, CN, O—(C₁-C₆)alkyl, (C₁-C₆)alkyl, NH₂, NH(C₁-C₆)alkyl,N[(C₁-C₆)alkyl]₂, SO₂CH₃, COOH, C(O)O—(C₁-C₆)alkyl, CONH₂,(C₁-C₆)alkylene-O—(C₁-C₆)alkyl, (C₁-C₆)alkylene-O—(C₆-C₁₀)aryl, orO—(C₁-C₆)alkylene-(C₆-C₁₀)aryl; orwherein (C₆-C₁₀)aryl is vicinally substituted by a O—(C₁-C₄)alkylene-Ogroup whereby a 5-8-membered ring is formed together with the carbonatoms the oxygen atoms are attached to; andwherein aryl substituents of (C₆-C₁₀)aryl, (C₅-C₁₀)heteroaryl,(C₃-C₈)heterocycloalkyl or (C₃-C₈)cycloalkyl groups may not be furthersubstituted by an aryl, heteroaryl, heterocycloalkyl, or(C₃-C₈)cycloalkyl containing group;their stereoisomeric and/or tautomeric forms and/or theirpharmaceutically acceptable salts thereof.

In another embodiment the present invention also relates to a compoundof formula (I) and/or its pharmaceutically acceptable salt for use as amedicament. It also relates to the use of at least one compound offormula (I) and/or a pharmaceutically acceptable salt thereof for thetreatment and/or prevention of Rho-Kinase mediated diseases such ashypertension, pulmonary hypertension, ocular hypertension, retinopathy,glaucoma, peripheral circulatory disorder, peripheral arterial occlusivedisease (PAOD), coronary heart disease, angina pectoris, hearthypertrophy, heart failure, ischemic diseases, ischemic organ failure(end organ damage), fibroid lung, fibroid liver, liver failure,nephropathy, renal failure, fibroid kidney, renal glomerulosclerosis,organ hypertrophy, asthma, chronic obstructive pulmonary disease (COPD),adult respiratory distress syndrome, thrombotic disorders, stroke,cerebral vasospasm, cerebral ischemia, pain, neuronal degeneration,spinal cord injury, Alzheimer's disease, premature birth, erectiledysfunction, endocrine dysfunctions, arteriosclerosis, prostatichypertrophy, diabetes and complications of diabetes, metabolic syndrome,blood vessel restenosis, atherosclerosis, inflammation, autoimmunediseases, AIDS, osteopathy, infection of digestive tracts with bacteria,sepsis or cancer development and progression. The invention furtherrelates to a medicament comprising an effective amount of at least onecompound of formula (I) and/or a pharmacologically acceptable saltthereof. Another object of the present invention is a method ofproducing a compound of formula (I).

The term alkyl as used in (C₁-C₂)alkyl, (C₁-C₄)alkyl, or (C₁-C₆)alkyland the corresponding alkylene substituents are understood as ahydrocarbon residue which can be linear, i.e. straight-chain, orbranched and has 1, 2, 3, 4, 5, or 6 carbon atoms, respectively. Thisalso applies if an alkyl group occurs as a substituent on another group,for example in an alkoxy group (O-alkyl), S-alkyl or a—O(C₁-C₆)alkylene-O—, an alkoxycarbonyl group or an arylalkyl group.Examples of alkyl groups are methyl, ethyl, propyl, butyl, pentyl orhexyl, the n-isomers of all these groups, isopropyl, isobutyl,1-methylbutyl, isopentyl, neopentyl, 2,2-dimethylbutyl, 2-methylpentyl,3-methylpentyl, isohexyl, sec-butyl, tert-butyl or tert-pentyl. Alkyl oralkylene groups may optionally be halogenated once or more, e.g. alkylgroups may be fluorinated, e.g. perfluorinated. Examples of halogenatedalkyl groups are CH₂F, CHF₂, CF₃ and CH₂CF₃, OCF₃, SCF₃, or—O—(CF₂)₂—O—.

The term (C₂-C₆)-alkenyl means a hydrocarbon residue whose carbon chainis straight-chain or branched and comprises 2 to 6 carbon atoms and has,depending on the chain length, 1, 2 or 3 double bonds, for example,vinyl, 1-propenyl, 2-propenyl (=allyl), 2-butenyl, 3-butenyl,2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl or 1,3-pentadienyl.The double bond may where possible have the E or Z orientation. Thedouble bonds may be both internal and terminal.

(C₂-C₆)-alkynyl groups are hydrocarbon residue whose carbon chain isstraight-chain or branched and comprises 2 to 6 carbon atoms and have,depending on the chain length, 1 or 2 triple bonds, for example,ethynyl, 1-propynyl, 2-propynyl (=propargyl) or 2-butynyl. The triplebonds may be both internal and terminal.

Halogen means fluoro (F), chloro (Cl), bromo (Br) or iodo (I).

The term (C₁-C₈)heteroalkyl or the corresponding (C₁-C₈)heteroalkylenesubstituents are understood as (C₁-C₈)alkyl or (C₁-C₈)alkylene groupswherein at least one carbon atom, preferably one or two carbon atoms,more preferred one carbon atom, is replaced by a group selected from O,NH, or S and wherein the nitrogen and sulfur atoms may optionally beoxidized. The heteroatom may be placed at any position of the alkyl oralkylene group. Examples of (C₁-C₈)heteroalkyl groups include—CH₂—O—CH₃, —CH₂—CH₂—O—CH₂—CH₃, —CH₂—NH—CH₂—CH₃,—CH₂—N(CH₂—CH₃)₂—CH₂—CH₂—CH₂—O—CH₃, —CH₂—CH₂—CH₂—S—CH₃, —CH₂—O—CH(CH₃)₂,—CH₂—O—CH₂—CH₂—O—CH₃ or O—CH₂—CH₃.

(C₃-C₈)cycloalkyl groups are cyclic alkyl groups containing 3, 4, 5, 6,7 or 8 ring carbon atoms like cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cyclooctyl, which can also be substituted and/or contain 1or 2 double bounds (unsaturated cycloalkyl groups) like, for example,cyclopentenyl or cyclohexenyl, which can be bonded via any carbon atom.

A (C₆-C₁₀)aryl group means an aromatic ring or a ring system whichcomprises two aromatic rings which are fused or otherwise linked orwhich comprises two fused aromatic rings wherein one ring is saturatedor partly saturated, i.e contains at least one C—C single bond, forexample a phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha- orbeta-tetralon-, indanyl- or indan-1-on-yl group. A preferred(C₆-C₁₀)aryl group is phenyl.

(C₃-C₈)heterocycloalkyl group means a saturated (contains no doublebonds) monocyclic carbon ring system containing 3, 4, 5, 6, 7 or 8 ringatoms in which one or more carbon atoms can be replaced by one or moreheteroatoms such as, for example 1, 2 or 3 nitrogen atoms, 1 or 2 oxygenatoms, 1 or 2 sulfur atoms or combinations of different hetero atoms.The heterocycloalkyl residues can be bound at any positions, for exampleon the 1-position, 2-position, 3-position, 4-position, 5-position,6-position, 7-position or 8-position. Also included are thecorresponding N-oxides, sulfoxides or sulfones of these compounds.

Examples of (C₃-C₈)heterocycloalkyl groups are oxiranyl, oxetanyl,aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxolanyl, forexample 1,3-dioxolanyl, dioxanyl, for example 1,4-dioxanyl, piperidinyl,pyrrolidinyl, imidazolidinyl, triazolidinyl, hexahydropyrimidinyl,piperazinyl, triazinanyl, for example, 1,3,5-triazinanyl,1,2,3-triazinanyl or 1,2,4-triazinanyl, tetrahydrothiophenyl,tetrahydro-thiopyranyl, dithiolanyl, for example 1,3-dithiolanyl,dithianyl, thiazolidinyl, oxazolidinyl, oxathiolanyl, for example1,3-oxathiolanyl, morpholinyl or thiomorpholinyl, diazepanyl, forexample 1,4-diazepanyl.

A preferred (C₃-C₈)heterocycloalkyl group is morpholinyl, pyrrolidinyl,piperazinyl, piperidinyl, oxetanyl or tetrahydropyranyl.

(C₅-C₁₀)heteroaryl means a mono- or bicyclic ring system in which one ormore carbon atoms can be replaced by one or more heteroatoms such as,for example 1, 2, 3 or 4 nitrogen atoms, 1 or 2 oxygen atoms, 1 or 2sulfur atoms or combinations of different hetero atoms. The heteroarylresidues can be bound at any position, for example on the 1-position,2-position, 3-position, 4-position, 5-position, 6-position, 7-positionor 8-position. (C₅-C₁₀)heteroaryl groups may be an (1) aromaticmonocyclic or bicyclic ring system or (2) a bicyclic ring system whereinone ring is aromatic and the second ring is at least partiallysaturated.

Also included are the corresponding N-oxides, sulfoxides or sulfones ofthese compounds.

Suitable (C₅-C₁₀)heteroaryl groups are benzimidazolyl, benzofuryl,benzothienyl, azaindolyl, benzothiophenyl, benzoxazolyl, benzthiazolyl,benztriazolyl, benzisoxazolyl, benzisothiazolyl, carbolinyl, cinnolinyl,chromanyl, chromenyl, naphthyridinyl, phthalazinyl, pyridoimidazolyl,pteridinyl, purynyl, quinazolinyl, quinoxalinyl, quinolinyl,isoquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolinyl,indolizinyl, indolyl, furyl, furazanyl, thienyl, imidazolyl,imidazolinyl, 1H-indazolyl, pyrazolyl, oxazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, isoxazolyl,thiazolyl, isothiazolyl, pyridyl, triazolyl, pyrazinyl, pyrimidinyl,pyridazinyl, pyrazolinyl, pyrrolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl.

Pyridyl stands both for 2-, 3- and 4-pyridyl. Thienyl stands both for 2-and 3-thienyl. Furyl stands both for 2- and 3-furyl. Also included arethe corresponding N-oxides of these compounds, for example, 1-oxy-2-, 3-or 4-pyridyl.

Substitutions in (C₅-C₁₀)heteroaryl residues can occur on free carbonatoms or on nitrogen atoms.

Preferred examples of (C₅-C₁₀)heteroaryl residues are benzofuryl,quinolinyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, pyridyl, triazolyl, oxadiazolyl, pyrazinyl,pyrimidinyl, pyridazinyl and tetrazolyl.

A preferred (C₅-C₁₀)heteroaryl is a (C₅-C₆)heteroaryl group. Preferred(C₅-C₆)heteroaryl residues are furyl, thienyl, imidazolyl, pyrazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, triazolyl,oxadiazolyl, pyrazinyl, pyrimidinyl, and pyridazinyl. Preferred examplesof (C₅-C₆)heteroaryl residues are 2- or 3-thienyl, 2- or 3-furyl, 1-, 2-or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl,1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 2-, 4-or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 1,2,3-oxadiazol-4- or -5-yl,1,2,4-oxadiazol-3- or -5-yl, 1,3,4-oxadiazol-2- or -5-yl, 2-, 4- or5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5-or 6-pyrimidinyl, 3- or 4-pyridazinyl, or pyrazinyl.

In residues R₃ to R₁₅ (C₆-C₁₀)aryl and (C₅-C₁₀)heteroaryl residues areunsubstituted or, if not specified otherwise, optionally substituted oneor more times, preferably one to three times, more preferably once, by agroup independently selected from halogen, OH, NO₂, N₃, CN,C(O)—(C₁-C₆)alkyl, C(O)—(C₆-C₁₀)aryl, COOH, COO(C₁-C₆)alkyl, CONH₂,CONH(C₁-C₆)alkyl, CON[(C₁-C₆)alkyl]₂, (C₃-C₈)cycloalkyl, (C₁-C₆)alkyl,(C₁-C₆)alkylene-NH(C₁-C₆)alkyl, (C₁-C₆)alkylene-N[(C₁-C₆)alkyl]₂,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, O—(C₁-C₆)alkyl, O—C(O)—(C₁-C₆)alkyl,PO₃H₂, SO₃H, SO₂—NH₂, SO₂NH(C₁-C₆)alkyl, SO₂N[(C₁-C₆)alkyl]₂,S—(C₁-C₆)alkyl, SO—(C₁-C₆)alkyl, SO₂—(C₁-C₆)alkyl,SO₂—N═CH—N[(C₁-C₆)alkyl]₂, SF₅, C(NH)(NH₂), NH₂, NH—(C₁-C₆)alkyl,N[(C₁-C₆)alkyl]₂, NH—C(O)—(C₁-C₆)alkyl, NH—C(O)O—(C₁-C₆)alkyl,NH—SO₂—(C₁-C₆)alkyl, NH—SO₂—(C₆-C₁₀)aryl, NH—SO₂—(C₅-C₁₀)heteroaryl,NH—SO₂—(C₃-C₈)heterocycloalkyl, N(C₁-C₆)alkyl-C(O)—(C₁-C₆)alkyl,N(C₁-C₆)alkyl-C(O)O—(C₁-C₆)alkyl, N(C₁-C₆)alkyl-C(O)—NH—(C₁-C₆)alkyl],(C₆-C₁₀)aryl, (C₁-C₆)alkylene-(C₆-C₁₀)aryl, O—(C₆-C₁₀)aryl,O—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, (C₅-C₁₀)heteroaryl,(C₃-C₈)heterocycloalkyl, (C₁-C₆)alkylene-(C₅-C₁₀)heteroaryl,(C₁-C₆)alkylene-(C₃-C₈)heterocycloalkyl,O—(C₁-C₆)alkylene-(C₅-C₁₀)heteroaryl,O—(C₁-C₆)alkylene-(C₃-C₈)heterocycloalkyl, wherein said (C₆-C₁₀)aryl,(C₅-C₁₀)heteroaryl, (C₃-C₈)heterocycloalkyl or (C₃-C₈)cycloalkyl may besubstituted one to three times by a group independently selected fromhalogen, OH, NO₂, CN, O—(C₁-C₆)alkyl, (C₁-C₆)alkyl, NH₂, NH(C₁-C₆)alkyl,N[(C₁-C₆)alkyl]₂, SO₂CH₃, COOH, C(O)O—(C₁-C₆)alkyl, CONH₂,(C₁-C₆)alkylene-O—(C₁-C₆)alkyl, (C₁-C₆)alkylene-O—(C₆-C₁₀)aryl, orO—(C₁-C₆)alkylene-(C₆-C₁₀)aryl; or

wherein (C₆-C₁₀)aryl is vicinally substituted by a O—(C₁-C₄)alkylene-Ogroup whereby a 5-8-membered ring is formed together with the carbonatoms the oxygen atoms are attached to; andwherein aryl substituents of (C₆-C₁₀)aryl, (C₅-C₁₀)heteroaryl,(C₃-C₈)heterocycloalkyl or (C₃-C₈)cycloalkyl groups may not be furthersubstituted by an aryl, heteroaryl, heterocycloalkyl, or(C₃-C₈)cycloalkyl containing group.

Preferred substituents for (C₆-C₁₀)aryl and (C₅-C₁₀)heteroaryl groupsare OH, (C₁-C₄)alkyl, O—(C₁-C₄)alkyl, O-phenyl, phenyl,C(O)O—(C₁-C₆)alkyl, C(O)OH, C(O)—(C₁-C₄)alkyl, halogen, NO₂, SO₂NH₂, CN,SO₂—(C₁-C₄)alkyl, SO₂—N═CH—N[(C₁-C₆)alkyl]₂, NH—SO₂—(C₁-C₄)alkyl, NH₂,NH—C(O)—(C₁-C₄)alkyl, (C₃-C₈)cycloalkyl, (C₁-C₄)alkyl-OH,C(O)N[(C₁-C₄)alkyl]₂, C(O)NH(C₁-C₆)alkyl, C(O)NH₂, N[(C₁-C₄)alkyl]₂,(C₁-C₄)alkylene-N[(C₁-C₄)alkyl]₂, (C₁-C₄)alkylene-O—(C₁-C₄)alkyl,(C₅-C₆)heteroaryl, (C₃-C₈)heterocycloalkyl,(C₁-C₄)alkylene-(C₆-C₁₀)aryl, wherein the (C₆-C₁₀)aryl may be furthersubstituted one to three times, preferably once, by halogen,(C₁-C₄)alkyl, O—(C₁-C₄)alkyl, (C₁-C₄)alkylene-O—(C₁-C₆)alkyl,(C₆-C₁₀)aryl, O—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, or may be vicinallysubstituted by a O—(C₁-C₄)alkylene-O group whereby a 5-8-membered ringis formed together with the carbon atoms the oxygen atoms are attachedto.

More preferred substituents for (C₆-C₁₀)aryl and (C₅-C₁₀)heteroaryl areOH, halogen, CN, phenyl, O-phenyl, NH—C(O)—(C₁-C₄)alkyl,C(O)—(C₁-C₄)alkyl, C(O)—O(C₁-C₄)alkyl, (C₁-C₄)alkyl, O—(C₁-C₄)alkyl,CONH₂, SO₂—NH₂, SO₂—(C₁-C₄)alkyl or SO₂—N═CH—N[(C₁-C₄)alkyl]₂,(C₁-C₄)alkylene-phenyl, (C₁-C₄)alkylene-O—(C₁-C₄)alkyl or(C₅-C₆)heteroaryl, wherein the phenyl is unsubstituted or optionallysubstituted one to three times, preferably once, by OH, halogen,(C₁-C₄)alkyl or O—(C₁-C₄)alkyl. Even more preferred substituents for(C₆-C₁₀)aryl and (C₅-C₁₀)heteroaryl are OH, halogen, CN, phenyl,O-phenyl, NH—C(O)—(C₁-C₄)alkyl especially NH—C(O)—CH₃, C(O)—(C₁-C₄)alkylespecially C(O)—CH₃, C(O)—O(C₁-C₄)alkyl especially C(O)—OCH₃,(C₁-C₄)alkyl especially CH₃ or CF₃, O—(C₁-C₄)alkyl especially O—CH₃,CONH₂, SO₂—NH₂, SO₂—(C₁-C₄)alkyl especially SO₂—CH₃ or SO₂—CF₃; orSO₂—N═CH—N[(C₁-C₄)alkyl]₂ especially SO₂—N═CH—N[(CH₃)₂,

wherein the phenyl is unsubstituted or optionally substituted one tothree times, preferably once, by OH, halogen, (C₁-C₄)alkyl orO—(C₁-C₄)alkyl.

More especially preferred substituents for (C₆-C₁₀)aryl and(C₅-C₁₀)heteroaryl groups are OH, CN, (C₁-C₄)alkyl especially CH₃ orCF₃, O(C₁-C₄)alkyl especially O—CH₃, halogen or phenyl, wherein thephenyl may be further substituted one to three times, preferably once,by OH, halogen, (C₁-C₄)alkyl especially CH₃ or CF₃, or O—(C₁-C₄)alkylespecially O—CH₃.

Most preferred substituents for (C₆-C₁₀)aryl and (C₅-C₁₀)heteroarylgroups are OH, CN, halogen, (C₁-C₄)alkyl especially CH₃ or CF₃,O(C₁-C₄)alkyl especially O—CH₃, or halogen.

In monosubstituted phenyl groups the substituent can be located in the2-position, the 3-position or the 4-position, with the 3-position andthe 4-position being preferred. If a phenyl group carries twosubstituents, they can be located in 2,3-position, 2,4-position,2,5-position, 2,6-position, 3,4-position or 3,5-position. In phenylgroups carrying three substituents the substituents can be located in2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position,2,4,6-position, or 3,4,5-position.

The above statements relating to phenyl groups correspondingly apply todivalent groups derived from phenyl groups, i.e. phenylene which can beunsubstituted or substituted 1,2-phenylene, 1,3-phenylene or1,4-phenylene. The above statements also correspondingly apply to thearyl subgroup in arylalkylene groups. Examples of arylalkylene groupswhich can also be unsubstituted or substituted in the aryl subgroup aswell as in the alkylene subgroup, are benzyl, 1-phenylethylene,2-phenylethylene, 3-phenylpropylene, 4-phenylbutylene,1-methyl-3-phenyl-propylene.

In residues R₃ to R₁₅ an alkyl or alkylene is unsubstituted or, if notspecified otherwise, optionally substituted one or more times byhalogen. If substituted, alkyl or alkylene is preferably substituted oneto three times by halogen selected from chloro or bromo but may besubstituted by fluoro once or more, e.g. being perfluorinated.Preferably halogen is fluoro. Preferably alkylene is not halogenated.More preferred an alkyl or alkylene is not halogenated.

In residues R₃ to R₁₅ alkyl or alkylene is unsubstituted or, if notspecified otherwise, optionally substituted one or more times by a groupselected independently from OH, OCH₃, C(O)OH, C(O)OCH₃, NH₂, NHCH₃,N(CH₃)₂, C(O)NH₂, C(O)NHCH₃ or C(O)N(CH₃)₂. If substituted, the numberof substituents is preferably between 1, 2, 3 or 4, more preferably 1 or2 with 1 being even more preferred. Preferably an alkylene is notsubstituted by one of these groups. More preferably an alkyl or alkyleneis not substituted by one of these groups. Preferably alkyl or alkylenein R₃, R₄, R₅, R₇ and R₈ are not substituted. In a further embodimentalkyl or alkylene in R₄ to R₁₅ is not substituted by one of thesegroups.

In residues R₃ to R₁₅ cycloalkyl or heterocycloalkyl is unsubstitutedor, if not specified otherwise, optionally substituted one or more timesby (C₁-C₆)alkyl, halogen, OH, OCH₃, C(O)OH, C(O)OCH₃, NH₂, NHCH₃,N(CH₃)₂, C(O)NH₂, C(O)NHCH₃ or C(O)N(CH₃)₂. If substituted, the numberof substituents is preferably between 1, 2, 3 or 4, more preferably 1 or2 with 1 being even more preferred. Preferably cycloalkyl orheterocycloalkyl in R₃ to R₉ are not substituted. In a furtherembodiment cycloalkyl or heterocycloalkyl in R₃ to R₁₅ are notsubstituted. In a preferred embodiment a heterocycloalkyl is notsubstituted. In another embodiment cycloalkyl is not substituted.

The general and preferred substituents of (C₆-C₁₀)aryl,(C₅-C₁₀)heteroaryl, (C₃-C₈)heterocycloalkyl and (C₃-C₈)cycloalkyl groupsas defined before may be combined with the general and preferreddefinitions of R₁, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄,R₁₅, n, s, m, r, p and L as described in the following embodiments of acompound of formula (I).

The following embodiments of a compound of formula (I) do furthercharacterize and are part of the present invention.

In one embodiment of a compound of formula (I) R₁ is H and the compoundis characterized by the formula (II)

In another embodiment of the present invention R₁ is OH and the compoundis characterized by the formula (IIIa)

The isoquinoline derivative of formula (I), wherein R₁ is OH, includesthe corresponding tautomeric 1-isoquinolone derivative which ischaracterized by the formula (IIIb)

This tautomeric form is also an embodiment of the present invention.

In a further embodiment R₁ is NH₂ and the compound is characterized bythe formula (IV)

The following further embodiments equally refer to the compounds offormula (I), (II), (IIIa), (IIIb) and (IV).

In a preferred embodiment R₁ is H or OH; more preferably R₁ is OH.

In one embodiment R₃ is preferably H, halogen, (C₁-C₆)alkyl, or NHR′. Inanother more preferred embodiment R₃ is H, halogen, unsubstituted orsubstituted NH—(C₅-C₆)heteroaryl, unsubstituted or substitutedNH—(C₃-C₈)heterocycloalkyl or unsubstituted or substituted NH-phenyl. Ina even more preferred embodiment R₃ is unsubstituted or substitutedNH—(C₅-C₆)heteroaryl containing one or more N atoms, or unsubstituted orsubstituted NH-phenyl. In a most preferred embodiment R₃ is H. Examplesof NHR′ substituents in R₃ are

The asterisk (*) denotes where the bond is connected to the C-atom ofthe ring.

In a preferred embodiment R₄ is H, halogen, (C₁-C₆)alkyl, or(C₁-C₂)-alkylene-phenyl. In a more preferred embodiment R₄ is H, halogenor unsubstituted or substituted (C₁-C₄)alkyl or (C₁-C₂)-alkylene-phenyl,preferably unsubstituted (C₁-C₄)alkyl or (C₁-C₂)-alkylene-phenyl. Evenmore preferred R₄ is H or halogen, with H being most preferred.

In a preferred embodiment R₅ is H, CN, halogen, unsubstituted orsubstituted (C₁-C₆)alkyl, unsubstituted or substituted (C₆-C₁₀)aryl,substituted or unsubstituted (C₃-C₈)cycloalkyl or unsubstituted orsubstituted (C₅-C₁₀)heteroaryl. (C₆-C₁₀)aryl is preferably phenyl.Examples of R₅ are hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl,phenyl, thienyl or pyridyl, nitrile, (p-methoxy)-phenyl, N-aniline,cyclopropyl, tetrazol, 4-methoxy-aniline. In a more preferred embodiment(C₁-C₆)alkyl, (C₆-C₁₀)aryl, (C₃-C₈)cycloalkyl or (C₅-C₁₀)heteroaryl areunsubstituted. In an even more preferred embodiment R₅ is H, halogen,methyl, ethyl, phenyl, thienyl, or pyridyl, more specifically H,halogen, methyl, or ethyl. Most preferred R₅ is H.

In a preferred embodiment R₇ is H, halogen, nitrile, unsubstituted orsubstituted (C₁-C₆)alkyl, unsubstituted or substituted O—(C₁-C₆)alkyl,or unsubstituted or substituted R′. In a more preferred embodiment R₇ isH, halogen, nitrile, unsubstituted or substituted (C₁-C₄)alkyl,unsubstituted or substituted O—(C₁-C₄)alkyl, unsubstituted orsubstituted phenyl, unsubstituted or substituted (C₅-C₆)heteroaryl, orunsubstituted or substituted (C₃-C₆)cycloalkyl. Preferably, alkyl,phenyl or (C₅-C₆)heteroaryl are unsubstituted.

In an even more preferred embodiment R₇ is H, fluoro, chloro, bromo,methyl, ethyl, methoxy, phenyl, nitrile, cyclopropyl, or thienyl. Morepreferably R₇ is H, fluoro, chloro, bromo, methyl or methoxy, inparticular H, methyl or chloro. Most preferred R₇ is chloro.

In a preferred embodiment R₈ is H, Cl, F, methyl or ethyl. In a morepreferred embodiment R₈ is H.

In a preferred embodiment R₉ is R′, OH, halogen, (C₁-C₆)alkyl,(C₁-C₆)alkylene-R′, (C₂-C₆)alkenyl, (C₁-C₆)alkylene-C(O)NH—R′,(C₁-C₆)alkylene-C(O)NH—(C₁-C₆)alkyl, COOH, CONH₂, C(O)NH—(C₁-C₆)alkyl,C(O)NHR′, C(O)—NH—(C₁-C₆)alkynyl, C(O)—NH(C₁-C₆)alkylene-R′, orC(O)N[(C₁-C₆)alkyl]₂; wherein alkyl, alkylene and R″ are unsubstitutedor substituted. In a more preferred embodiment R₉ is OH, halogen,(C₁-C₆)alkyl, (C₁-C₆)alkylene-R′, (C₂-C₆)alkenyl, COOH, CONH₂,C(O)NH—(C₁-C₆)alkyl, C(O)NHR′, or C(O)N[(C₁-C₆)alkyl]₂, wherein alkyl,alkylene and R′ are unsubstituted or substituted. More preferably R₉ isOH, halogen, (C₁-C₆)alkyl, COOH, CONH₂, or O—CH₃, wherein alkyl isunsubstituted or substituted. In an even more preferred embodiment R₉ isunsubstituted or substituted (C₁-C₆)alkyl, preferably R₉ isunsubstituted (C₁-C₆)alkyl.

R₉ may be bound to any carbon atom of the ring including the positionwhere the linker group L is bound.

As examples for these embodiments, R₉ is methyl, ethyl, propyl,isopropyl,

The asterisk (*) denotes where the bond is connected to the C-atom ofthe ring.

In a preferred embodiment R₁₀ is

H,

(C₆-C₁₀)aryl,O—(C₆-C₁₀)aryl,O—(C₁-C₂)alkylene-(C₆-C₁₀)aryl, or(C₅-C₆)heteroaryl,wherein (C₆-C₁₀)aryl or (C₅-C₆)heteroaryl are unsubstituted orsubstituted. Preferably (C₆-C₁₀)aryl is phenyl.

In a more preferred embodiment R₁₀ is H, phenyl, O-phenyl, or(C₅-C₆)heteroaryl, wherein phenyl or (C₅-C₆)heteroaryl is unsubstitutedor substituted.

In a more preferred embodiment R₁₀ is H or phenyl optionally substituted1, 2 or 3 times, preferably once, by a group independently selected fromC(O)NH₂, OH, CN, halogen, (C₁-C₆)alkyl or O—(C₁-C₆)alkyl, wherein alkylis unsubstituted or optionally substituted once or more by halogen.

In an even more preferred embodiment R₁₀ is H or phenyl optionallysubstituted independently by a group selected from (C₁-C₆)alkyl, F, Cl,Br, OMe or CF₃.

In a most preferred embodiment R₁₀ is H. In still another most preferredembodiment R₁₀ is phenyl. Examples for embodiments of R₁₀ residues are

In a preferred embodiment R₁₁ is

H,

(C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, or(C₅-C₆)heteroaryl, preferably H or (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, or (C₅-C₁₀)heteroaryl are unsubstituted orsubstituted, preferably unsubstituted.

In a more preferred embodiment R₁₁ is H or (C₁-C₆)alkyl, wherein(C₁-C₆)alkyl is unsubstituted or substituted, preferably unsubstituted.Even more preferred R₁₁ is H or methyl. Most preferably R₁₁ is H.

In a preferred embodiment R₁₂ is

(C₁-C₆)alkyl, wherein optionally one or more hydrogen are substituted byfluoro;(C₃-C₈)cycloalkyl,(C₅-C₆)heteroaryl, or(C₆-C₁₀)aryl, wherein (C₃-C₈)cycloalkyl, (C₅-C₆)heteroaryl and(C₆-C₁₀)aryl are unsubstituted or substituted, preferably(C₃-C₈)cycloalkyl, and (C₅-C₆)heteroaryl are unsubstituted. Preferably(C₆-C₁₀)aryl is phenyl which is unsubstituted or optionally substitutedonce or twice by a group selected independently of each other fromhalogen, (C₁-C₄)alkyl or O—(C₁-C₄)alkyl, wherein (C₁-C₄)alkyl mayoptionally be substituted by fluoro.

In a preferred embodiment R₁₂ is methyl, ethyl, propyl, isopropyl,isobutyl, cyclopropyl, trifluoromethyl, thiazolyl or phenylunsubstituted or substituted by (C₁-C₄)alkyl or halogen. More preferred,R₁₂ is methyl, ethyl, propyl, isopropyl, isobutyl, cyclopropyl, or isphenyl optionally substituted by methyl or halogen.

In another embodiment R₁₀ is H, R₁₁ is H and R₁₂ is phenyl optionallysubstituted 1, 2 or 3 times, preferably once, by a group independentlyselected from halogen, (C₁-C₆)alkyl or O—(C₁-C₆)alkyl, wherein alkyl isunsubstituted or optionally substituted once or more by halogen.

In another embodiment R₁₀ is phenyl optionally substituted 1, 2 or 3times, preferably once, by a group independently selected from halogen,(C₁-C₆)alkyl or O—(C₁-C₆)alkyl, wherein alkyl is unsubstituted oroptionally substituted once or more by halogen; R₁₁ is H and R₁₂ isunsubstituted (C₃-C₈)cycloalkyl or (C₁-C₆)alkyl, wherein in the alkyloptionally one or more hydrogen are substituted by fluoro;(C₃-C₈)cycloalkyl, or phenyl.

In a further embodiment R₁₁ and R₁₂, together with the carbon atom towhich they are attached, form a (C₃-C₈)cycloalkyl ring, which isunsubstituted or substituted, preferably unsubstituted. More preferredthe ring is cyclopropyl.

In a further embodiment R₁₁ and R₁₂, together with the carbon atom towhich they are attached, form a (C₃-C₈)heterocycloalkyl ring, which isunsubstituted or substituted. Preferably the formed heterocyclyl groupis oxetanyl, morpholinyl, piperidinyl, pyrrolidinyl or piperazinyl. Morepreferably the heterocyclyl group is morpholinyl or piperazinyl. Theformed heterocycloalkyl group is preferably unsubstituted.

In one embodiment of a compound of formula (I) R₁₃ and R₁₄ areindependently of each other

H, R′,

(C₁-C₆)alkyl,(C₁-C₆)alkylene-R′,(C₁-C₆)alkylene-O—(C₁-C₆)alkyl,(C₁-C₆)alkylene-O—R′,C(O)(C₁-C₆)alkyl,

C(O)R′,

C(O)(C₁-C₆)alkyene-R′,C(O)N[(C₁-C₆)alkyl]₂, whereinR′, (C₁-C₆)alkyl and (C₁-C₆)alkylene are unsubstituted or substituted.

In a further embodiment R₁₃ and R₁₄, together with the N-atom to whichthey are attached, form a (C₃-C₈)-heterocycloalkyl ring, which isunsubstituted or substituted. Preferably, a (C₃-C₈)-heterocycloalkyl isunsubstituted.

In a preferred embodiment of a compound of formula (I) R₁₃ and R₁₄ areindependently of each other

H,

(C₁-C₆)alkyl,(C₃-C₈)cycloalkyl,(C₁-C₄)alkylene-(C₃-C₈)cycloalkyl,(C₁-C₄)alkylene-(C₅-C₁₀)heteroaryl,(C₁-C₄)alkylene-(C₃-C₈)heterocycloalkyl,(C₁-C₄)alkylene-(C₆-C₁₀)aryl,(C₁-C₄)alkylene-O—(C₁-C₆)alkyl,C(O)(C₁-C₆)alkyl, orR₁₃ and R₁₄, together with the N-atom to which they are attached, form a(C₃-C₈) heterocycloalkyl group,wherein (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₁-C₄)alkylene,(C₅-C₁₀)heteroaryl, (C₃-C₈)heterocycloalkyl, (C₆-C₁₀)aryl areunsubstituted or substituted.

Preferably the formed heterocyclyl group in R₁₃ and R₁₄ is morpholinyl,piperidinyl, pyrrolidinyl or piperazinyl. More preferably theheterocyclyl group is morpholinyl or piperazinyl.

In a more preferred embodiment of a compound of formula (I)

R₁₃ is H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, or(C₁-C₄)alkylene-(C₃-C₈)cycloalkyl; and

R₁₄ is H,

(C₁-C₆)alkyl,(C₃-C₈)cycloalkyl,(C₁-C₄)alkylene-(C₃-C₈)cycloalkyl,(C₁-C₄)alkylene-(C₅-C₁₀)heteroaryl,(C₁-C₄)alkylene-(C₃-C₈)heterocycloalkyl,C₁-C₄)alkylene-(C₆-C₁₀)aryl,(C₁-C₄)alkylene-O—(C₁-C₆)alkyl, orC(O)(C₁-C₆)alkyl.wherein (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₁-C₄)alkylene,(C₃-C₈)heterocycloalkyl, (C₆-C₁₀)aryl are unsubstituted or substituted.

In an even more preferred embodiment of a compound of formula (I)

R₁₃ is H or (C₁-C₆)alkyl; and

R₁₄ is H,

(C₁-C₆)alkyl,(C₃-C₈)cycloalkyl,(C₁-C₄)alkylene-(C₃-C₈)cycloalkyl,(C₁-C₄)alkylene-(C₅-C₁₀)heteroaryl,(C₁-C₄)alkylene-(C₃-C₈)heterocycloalkyl,(C₁-C₄)alkylene-(C₆-C₁₀)aryl, or(C₁-C₄)alkylene-O—(C₁-C₆)alkyl.wherein (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₁-C₄)alkylene,(C₃-C₈)heterocycloalkyl, (C₆-C₁₀)aryl are unsubstituted or substituted.

More preferrably R₁₃ is H, (C₁-C₆)alkyl and

R₁₄ is H, (C₁-C₆)alkyl or (C₃-C₈)cycloalkyl, wherein (C₁-C₆)alkyl or(C₃-C₈)cycloalkyl are unsubstituted or substituted, preferablyunsubstituted.

In a further embodiment R₁₃ is H and

R₁₄ is H, (C₁-C₆)alkyl or (C₃-C₈)cycloalkylwherein (C₁-C₆)alkyl or (C₃-C₈)cycloalkyl are unsubstituted.

Most preferred R₁₃ and R₁₄ are H.

As examples for the before mentioned embodiments, R₁₃ or R₁₄ are,independently from each other, hydrogen, methyl, ethyl, propyl,isopropyl, 3-methyl-butyl, 2-methyl-propyl, butyl, pentyl,3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl or a substituent selectedfrom the group consisting of

The asterisk (*) denotes where the bond is connected to the N-atom ofthe amine.

In one embodiment R₁₅ is H or (C₁-C₆)alkyl, which is unsubstituted oroptionally substituted, more preferably R₁₅ is H or (C₁-C₄)alkyl, mostpreferably H. Preferably, the alkyl is unsubstituted.

In one embodiment of a compound of formula (I) R₆ is absent or thebicyclus or the adamantane formed with R₆ is selected from the group of

(the bond with the dotted line indicates the position of the—(CR₁₁R₁₂)_(r)NR₁₃R₁₄ residue)or

which is unsubstituted or optionally substituted by R₉. In a preferredembodiment the bicyclus or adamantane is unsubstituted (n is 0) or issubstituted once (n=1).

Preferably the unsubstituted or substituted adamantane has the followingstructure

The cis and trans isomers in these adamantane residues such as forexample in the structures

are included.

In one embodiment of a compound of formula (I) R₆ is absent, i.e. nobicyclus or adamantane is formed.

In one embodiment m is 2 and s is 2 resulting in a residue within acompound of formula (I) of the formula

in all their stereochemical forms.

In another embodiment m is 3 and s is 1 resulting in a residue within acompound of formula (I) of the formula

In a further embodiment m is 2 and s 1. In still another embodiment m is3 and s is 0. In yet another embodiment m is 4 and s is 0.

In one embodiment of a compound of formula (I) n is 0, 1, or 2. Morepreferred, n is 0 or 1. Most preferred n is 0.

In a preferred embodiment r is 1.

In another embodiment L is O(CH₂)_(p). In a further embodiment L isS(CH₂)_(p), S(O)(CH₂)_(p) or SO₂(CH₂)_(p). In another embodiment L isNH(CH₂)_(p), N[(C₁-C₆)alkyl](CH₂)_(p), N[(C₃-C₆)cycloalkyl](CH₂)_(p),N[(C₁-C₃)alkylene-aryl](CH₂)_(p) orN[(C₁-C₃)alkylene-(C₅-C₆)heteroaryl](CH₂)_(p) with NH(CH₂)_(p),N(C₁-C₆)alkyl-(CH₂)_(p) being more preferred. A preferred N(C₁-C₆)alkylis N(C₁-C₄)alkyl, more preferably NCH₃ or NCH₂CH₃ with NCH₃ being morepreferred. In a preferred embodiment L is O(CH₂)_(p). In anotherpreferred embodiment L is S(CH₂)_(p). In a further embodiment L isNH(CH₂)_(p). Most preferred L is O, S or NH with O being especiallypreferred.

Preferably p is 0, 1, 2, or 3, more preferred 0 or 1, with 0 being mostpreferred;

More preferably, m is 2 and s is 2 and L is O, S or NH, preferably O.

In a further embodiment the present invention relates to a compound offormula (I) selected from the group consisting of

-   6-[4-(1-Amino-propyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   6-[4-(1-Amino-cyclopropyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   6-{[4-(1-aminopropyl)-4-phenylcyclohexyl]oxy}-7-chloroisoquinolin-1(2H)-one,-   6-[4-(1-Amino-butyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   6-[4-(1-Amino-butyl)-4-(4-fluoro-phenyl)-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,-   6-[4-(1-Amino-propyl)-4-(4-bromo-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   6-[4-(1-Amino-propyl)-4-(2-bromo-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   6-[4-(1-Amino-propyl)-4-(4-trifluoromethyl-phenyl)-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,-   6-[4-(1-Amino-propyl)-4-(2-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   6-[4-(1-Amino-propyl)-4-(2-chloro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   6-[4-(1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one,-   6-[4-(1-Amino-ethyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   6-[4-(Amino-phenyl-methyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   6-[4-(1-Amino-2-methyl-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   6-[4-(1-Amino-3-methyl-butyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   6-[4-(Amino-phenyl-methyl)-4-phenyl-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,-   6-[4-(1-Amino-1-methyl-ethyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   6-[4-(1-Amino-cyclopropyl)-4-(2-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   6-[4-(1-Amino-ethyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   6-[4-(1-Amino-1-methyl-ethyl)-4-phenyl-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,-   6-(4-[amino(cyclopropyl)methyl]-4-phenyl-cyclohexyl}oxy)-7-chloroisoquinolin-1(2H)-one,-   6-[4-(1-Amino-propyl)-4-(4-isopropyl-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   6-[4-(1-Amino-propyl)-4-(3-methoxy)-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   6-[4-(1-Amino-propyl)-4-(3-bromo-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   6-[4-(1-Amino-2-methyl-propyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,    or-   6-[4-(1-Amino-propyl)-4-phenyl-cyclohexyloxy]-4-bromo-7-chloro-2H-isoquinolin-1-one;    their stereoisomeric and/or tautomeric forms and/or their    pharmaceutically acceptable salts thereof.

In a further embodiment a compound of formula (I) is selected from thegroup consisting of

-   cis-6-[4-(1-Amino-propyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   trans-6-[4-(1-amino-propyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-on,-   cis-6-[4-(1-Amino-cyclopropyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-{[4-(1-aminopropyl)-4-phenylcyclohexyl]oxy}-7-chloro-2H-isoquinolin-1-one,-   trans-6-[4-(1-amino-propyl)-4-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-butyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   trans-6-[4-(1-Amino-butyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-butyl)-4-(4-fluoro-phenyl)-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,-   trans-6-[4-(1-Amino-butyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amin-propyl)-4-(4-bromo-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-(2-bromo-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-(4-trifluoromethyl-phenyl)-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-(2-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-(2-chloro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-ethyl)-4-(4-fluoro-phenyl)-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,-   trans-6-[4-(1-Amino-ethyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-(3-bromo-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   trans-6-[4-(1-Amino-propyl)-4-(3-bromo-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-(3-methoxy)-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   trans-6-[4-(1-Amino-propyl)-4-(3-methoxy-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   trans-6-[4-(Amino-phenyl-methyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   trans-6-[4-(1-Amino-2-methyl-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   trans-6-[4-(1-Amino-3-methyl-butyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   trans-6-[4-(Amino-phenyl-methyl)-4-phenyl-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,-   trans-6-[4-(1-Amino-1-methyl-ethyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-cyclopropyl)-4-(2-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-ethyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-1-methyl-ethyl)-4-phenyl-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-(4-[amino(cyclopropyl)methyl]-4-phenyl-cyclo-hexyl}oxy)-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-(4-isopropyl-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-2-methyl-propyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,    and-   cis-6-[4-(1-Amino-propyl)-4-phenyl-cyclohexyloxy]-4-bromo-7-chloro-2H-isoquinolin-1-one,    and their stereoisomeric and/or tautomeric forms and/or their    pharmaceutically acceptable salts thereof.

In a further embodiment a compound of formula (I) is selected from thegroup of

-   trans-6-[4-((S)-Amino-phenyl-methyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   trans-6-[4-((R)-Amino-phenyl-methyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-((S)-1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-((R)-1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-((S)-Amino-cyclopropyl-methyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-((R)-Amino-cyclopropyl-methyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-((R)-Amino-cyclopropyl-methyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-((S)-Amino-cyclopropyl-methyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-((S)-1-Amino-ethyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-((R)-1-Amino-ethyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   6-{4-[(S)-Amino-(4-fluoro-phenyl)-methyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,-   6-{4-[(R)-Amino-(4-fluoro-phenyl)-methyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-((R)-1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,    and-   cis-6-[4-((S)-1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,    their tautomeric forms and/or pharmaceutically acceptable salts    thereof.

In a further embodiment a compound of formula (I) is selected from thegroup consisting of

-   cis-6-[4-(1-Amino-propyl)-4-pyridin-2-yl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-(2,4-difluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-(4-fluoro-2-methyl-phenyl)cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-(3,5-difluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-(3,4-difluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-o-tolyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-(2-trifluoromethoxy-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-(4-fluoro-3-methoxy-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-(3-ethoxy-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-(3-methoxy-4-methyl-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-(3,4-difluoro-phenyl)-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-(3,5-difluoro-phenyl)-cyclohexyloxy]-7-fluoro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-(3,4-difluoro-phenyl)-cyclohexyloxy]-7-fluoro-5-methyl-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-(3,5-difluoro-phenyl)-cyclohexyloxy]-7-methoxy-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-(2-methoxy-phenyl)-cyclohexyloxy]-7-chloro-2H    isoquinolin-1-one-   cis-6-[4-(1-Amino-propyl)-4-(4-trifluoro-methoxy-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-1-methyl-ethyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-(3,5-difluoro-phenyl)-cyclohexyloxy]-4-benzyl-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-(3,5-difluoro-phenyl)-cyclohexyloxy]-5-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-(3,5-difluoro-phenyl)-cyclohexyloxy]-5,7-dimethyl-2H-isoquinolin-1-one,-   cis-6-[4-(Amino-cyclopropyl-methyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-(3-trifluoromethyl-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-(3-trifluoromethoxy-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-(3-trifluoromethoxy-phenyl)-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-(3-trifluoromethyl-phenyl)-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-fluoro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-fluoro-5-methyl-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-propyl)-4-phenyl-cyclohexyloxy]-4-benzyl-7-chloro-2H-isoquinolin-1-one,-   cis-4-[1-(1-Amino-propyl)-4-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-cyclohexyl]-benzonitrile,-   cis-3-[1-(1-Amino-propyl)-4-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-cyclohexyl]benzonitrile,-   6-[cis-4-(1-Amino-propyl)-4-(3-methanesulfonyl-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   6-[(1S,4S,5S)-5-(1-Amino-propyl)-5-phenyl-bicyclo[2.2.1]hept-2-yloxy]-7-chloro-2H-isoquinolin-1-one,-   6-[(1R,4R,5R)-5-(1-Amino-propyl)-5-phenyl-bicyclo[2.2.1]hept-2-yloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Benzylamino-propyl)-4-phenyl-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one,-   cis-6-[4-(1-Diethylamino-propyl)-4-phenyl-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one,-   cis-7-Methyl-6-[4-(1-propylamino-propyl)-4-(3-trifluoromethyl-phenyl)-cyclohexyloxy]-2H-isoquinolin-1-one,-   cis-6-[4-(1-Benzylamino-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-7-Chloro-6-[4-(1-isobutylamino-propyl)-4-phenyl-cyclohexyloxy]-2H-isoquinolin-1-one,-   cis-6-[4-(1-Butylamino-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-7-Chloro-6-{4-[1-(cyclopropylmethyl-amino)-propyl]-4-phenyl-cyclohexyloxy}-2H-isoquinolin-1-one,-   cis-6-[4-(2-Amino-propyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(2-Amino-butyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-2-fluoro-ethyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-(1-Amino-3-methoxy-propyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   6-[3-(1-Amino-propyl)-3-(4-fluoro-phenyl)-cyclobutyloxy]-7-chloro-2H-isoquinolin-1-one,    and-   6-[3-(1-Amino-propyl)-3-(4-fluoro-phenyl)-cyclopentyloxy]-7-chloro-2H-isoquinolin-1-one,    and their stereoisomeric and/or tautomeric forms and/or their    pharmaceutically acceptable salts thereof.

In a further embodiment a compound of formula (I) is selected from thegroup consisting of

-   cis-1-[4-(7-Chloro-isoquinolin-6-yloxy)-1-(3,4-difluoro-phenyl)-cyclohexyl]-propylamine,-   cis-1-[4-(7-Bromo-isoquinolin-6-yloxy)-1-(3,4-difluoro-phenyl)-cyclohexyl]-propylamine,-   cis-1-[1-(3,5-Difluoro-phenyl)-4-(5,7-dimethyl-isoquinolin-6-yloxy)-cyclohexyl]-propylamine,-   cis-1-[1-(3,5-Difluoro-phenyl)-4-(7-fluoro-5-methyl-isoquinolin-6-yloxy)-cyclohexyl]-propylamine,-   cis-1-[1-(3,4-Difluoro-phenyl)-4-(7-fluoro-isoquinolin-6-yloxy)-cyclohexyl]-propylamine,-   cis-1-[4-(7-Chloro-isoquinolin-6-yloxy)-1-(3,5-difluoro-phenyl)-cyclohexyl]-propylamine,-   cis-1-[4-(5-Chloro-isoquinolin-6-yloxy)-1-(3,5-difluoro-phenyl)-cyclohexyl]-propylamine,-   cis-1-[4-(7-Chloro-isoquinolin-6-yloxy)-1-phenyl-cyclohexyl]-propylamine,-   cis-1-[4-(5,7-Dimethyl-isoquinolin-6-yloxy)-1-phenyl-cyclohexyl]-propylamine,-   cis-1-[4-(7-Fluoro-isoquinolin-6-yloxy)-1-phenyl-cyclohexyl]-propylamine,-   cis-1-[4-(5-Chloro-isoquinolin-6-yloxy)-1-phenyl-cyclohexyl]-propylamine,-   cis-1-[4-(7-Fluoro-5-methyl-isoquinolin-6-yloxy)-1-phenyl-cyclohexyl]-propylamine,-   cis-1-[4-(7-Bromo-isoquinolin-6-yloxy)-1-phenyl-cyclohexyl]-propylamine,-   cis-1-[4-(7-Methyl-isoquinolin-6-yloxy)-1-phenyl-cyclohexyl]-propylamine,-   cis-6-[4-(1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-isoquinolin-1-ylamine,-   [4-(1-Amino-propyl)-4-(4-methoxy-phenyl)-cyclohexyl]-isoquinolin-6-yl-amine,    and-   1-Amino-[4-(1-amino-propyl)-4-(4-methoxy-phenyl)-cyclohexyl]-isoquinolin-6-yl-amine,    and their stereoisomeric and/or tautomeric forms and/or their    pharmaceutically acceptable salts thereof.

In a further embodiment the present invention relates to a compound offormula (I) selected from the group consisting of

-   6-[4-(1-Amino-1-phenyl-ethyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   6-{-4-[Amino-(4-methoxy-phenyl)-methyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,-   6-{4-[Amino-(4-fluoro-phenyl)-methyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,-   6-[4-(Amino-p-tolyl-methyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,    or-   6-[4-(Amino-phenyl-methyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,    their stereoisomeric and/or tautomeric forms and/or their    pharmaceutically acceptable salts thereof.

In a further embodiment a compound of formula (I) is selected from thegroup consisting of

-   6-{-4-[1-Amino-1-(4-fluoro-phenyl)-ethyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,-   6-{4-[1-Amino-1-(4-methoxy-phenyl)-ethyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,-   6-{4-[1-Amino-1-cyclopentyl-ethyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,-   6-{4-[1-Amino-1-ethyl-propyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,-   6-{4-[1-Amino-1-cyclopropyl-ethyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,-   6-{4-[1-Amino-1-n-propyl-ethyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,-   6-[4-(1-Amino-propyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,    and-   6-[4-(Amino-cyclopropyl-methyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,    their stereoisomeric and/or tautomeric forms and/or their    pharmaceutically acceptable salts thereof.

In any embodiments of the present invention one or more or all of thegroups contained in the compounds of formula (I) can independently ofeach other have any of the preferred, more preferred or most preferreddefinitions of the groups specified above or any one or some of thespecific denotations which are comprised by the definitions of thegroups and specified above, all combinations of preferred definitions,more preferred or most preferred and/or specific denotations being asubject of the present invention. Also with respect to all preferredembodiments the invention includes the compounds of the formula (I) inall stereoisomeric forms and mixtures of stereoisomeric forms in allratios, and their pharmaceutically acceptable salts.

Isoquinoline substitution pattern is numbered according to IUPAC rules:

The term isoquinolone and isoquinolinone are used synonymously. Allreferences to “compound(s) of formula (I)” herein refer to compound(s)of the formula (I), (II) (IIIa), (IIIb) and (IV) as described above, andtheir pharmaceutically acceptable salts, and/or to their stereoisomericforms, polymorphs and solvates. Physiologically functional derivativesas described herein are also included.

Pharmaceutically acceptable salts of compounds of the formula (I) meanboth their organic and inorganic salts as described in Remington'sPharmaceutical Sciences (17th edition, page 1418 (1985)). Because of thephysical and chemical stability and the solubility, preference is givenfor acidic groups inter alia to sodium, potassium, calcium and ammoniumsalts; preference is given for basic groups inter alia to salts ofmaleic acid, fumaric acid, succinic acid, malic acid, tartaric acid,methylsulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acidor of carboxylic acids or sulfonic acids, for example as hydrochlorides,hydrobromides, phosphates, sulfates, methanesulfonates, acetates,lactates, maleates, fumarates, malates, gluconates, and salts of aminoacids, of natural bases or carboxylic acids. The preparation ofpharmaceutically acceptable salts from compounds of the formula (I)which are capable of salt formation, including their stereoisomericforms, takes place in a manner known per se. The compounds of theformula (I) form stable alkali metal, alkaline earth metal or optionallysubstituted ammonium salts with basic reagents such as hydroxides,carbonates, bicarbonates, alcoholates and ammonia or organic bases, forexample trimethyl- or triethylamine, ethanolamine, diethanolamine ortriethanolamine, trometamol or else basic amino acids, for examplelysine, ornithine or arginine. Where the compounds of the formula (I)have basic groups, stable acid addition salts can also be prepared withstrong acids. Suitable pharmaceutically acceptable acid addition saltsof the compounds of the invention are salts of inorganic acids such ashydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric andsulfuric acid, and of organic acids such as, for example, acetic acid,benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic,glycolic, isethionic, lactic, lactobionic, maleic, malic,methanesulfonic, succinic, p-toluenesulfonic and tartaric acid. Thehydrochloride salt is a preferred salt.

Salts with a pharmaceutically unacceptable anion such as, for example,trifluoroacetate likewise belong within the framework of the inventionas useful intermediates for the preparation or purification ofpharmaceutically acceptable salts and/or for use in nontherapeutic, forexample in vitro, applications.

The present invention also includes physiologically functionalderivatives of a compound of formula (I). A physiologically functionalderivative as used herein refers to any physiologically toleratedderivative of a compound of the formula (I) of the invention, forexample an N-oxide, which on administration to a mammal such as, forexample, a human is able to form (directly or indirectly) a compound ofthe formula (I) or an active metabolite thereof.

Physiologically functional derivatives include prodrugs of the compoundsof the invention, as described, for example, in H. Okada et al., Chem.Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolized in vivoto a compound of the invention. These prodrugs may themselves be activeor not.

The invention relates to compounds of the formula (I) in the form oftheir stereoisomeric forms, which include racemates, enantiomericallyenriched mixtures, pure enantiomers and diastereomers and mixtures inany ratio thereof.

The compounds of the invention may also exist in various polymorphousforms, for example as amorphous and crystalline polymorphous forms. Allpolymorphous forms of the compounds of the invention belong within theframework of the invention and are a further aspect of the invention.

If radicals or substituents may occur more than once in the compounds ofthe formula (I), they may all, independently of one another, have thestated meaning and be identical or different.

The present invention also relates to the compounds of the formula (I)and/or their pharmaceutically acceptable salts and/or their prodrugs foruse as pharmaceuticals (or medicaments), to the use of the compounds ofthe formula (I) and/or their pharmaceutically acceptable salts and/ortheir prodrugs for the production of pharmaceuticals for the treatmentand/or prevention of diseases associated with Rho-kinase and/orRho-kinase mediated phosphorylation of myosin light chain phosphatase,i.e. for the treatment and/or prevention of hypertension, pulmonaryhypertension, ocular hypertension, retinopathy, and glaucoma, peripheralcirculatory disorder, peripheral arterial occlusive disease (PAOD),coronary heart disease, angina pectoris, heart hypertrophy, heartfailure, ischemic diseases, ischemic organ failure (end organ damage),fibroid lung, fibroid liver, liver failure, nephropathy, includinghypertension-induced, non-hypertension-induced, and diabeticnephropathies, renal failure, fibroid kidney, renal glomerulosclerosis,organ hypertrophy, asthma, chronic obstructive pulmonary disease (COPD),adult respiratory distress syndrome, thrombotic disorders, stroke,cerebral vasospasm, cerebral ischemia, pain, e.g. neuropathic pain,neuronal degeneration, spinal cord injury, Alzheimer's disease,premature birth, erectile dysfunction, endocrine dysfunctions,arteriosclerosis, prostatic hypertrophy, diabetes and complications ofdiabetes, metabolic syndrome, blood vessel restenosis, atherosclerosis,inflammation, autoimmune diseases, AIDS, osteopathy such asosteoporosis, infection of digestive tracts with bacteria, sepsis,cancer development and progression, e.g. cancers of the breast, colon,prostate, ovaries, brain and lung and their metastases.

In a further embodiment the invention also relates to the use of acompound of formula (I) and/or a pharmaceutically acceptable saltthereof for the treatment and/or prevention of hypertension, pulmonaryhypertension, fibroid liver, liver failure, nephropathy, renal failure,chronic obstructive pulmonary disease (COPD), cerebral vasospasm, pain,spinal cord injury, erectile dysfunction, blood vessel restenosis, orcancer development and progression.

In a further embodiment the invention also relates to the use of acompound of formula (I) and/or a pharmaceutically acceptable saltthereof for curative approaches associated with stem cell or inducedpluripotent stem cell treatment, improvement of recognition or fortreatment or prevention of depression, epilepsy, fibroid heart, renalpapillary necrosis, tubulo-interstitial dysfunction, multiple sclerosis,vessel stenosis for example carotid stenosis or lipid disorders.

The present invention furthermore relates to pharmaceutical preparations(or pharmaceutical compositions) which contain an effective amount of atleast one compound of the formula (I) and/or its pharmaceuticallyacceptable salts and a pharmaceutically acceptable carrier, i.e. one ormore pharmaceutically acceptable carrier substances (or vehicles) and/oradditives (or excipients).

The pharmaceuticals can be administered orally, for example in the formof pills, tablets, lacquered tablets, coated tablets, granules, hard andsoft gelatin capsules, solutions, syrups, emulsions, suspensions oraerosol mixtures. Administration, however, can also be carried outrectally, for example in the form of suppositories, or parenterally, forexample intravenously, intramuscularly or subcutaneously, in the form ofinjection solutions or infusion solutions, microcapsules, implants orrods, or percutaneously or topically, for example in the form ofointments, solutions or tinctures, or in other ways, for example in theform of aerosols or nasal sprays.

The pharmaceutical preparations according to the invention are preparedin a manner known per se and familiar to one skilled in the art,pharmaceutically acceptable inert inorganic and/or organic carriersubstances and/or additives being used in addition to the compound(s) ofthe formula (I) and/or its (their) pharmaceutically acceptable saltsand/or its (their) prodrugs. For the production of pills, tablets,coated tablets and hard gelatin capsules it is possible to use, forexample, lactose, corn starch or derivatives thereof, talc, stearic acidor its salts, etc. Carrier substances for soft gelatin capsules andsuppositories are, for example, fats, waxes, semisolid and liquidpolyols, natural or hardened oils, etc. Suitable carrier substances forthe production of solutions, for example injection solutions, or ofemulsions or syrups are, for example, water, saline, alcohols, glycerol,polyols, sucrose, invert sugar, glucose, vegetable oils, etc. Suitablecarrier substances for microcapsules, implants or rods are, for example,copolymers of glycolic acid and lactic acid. The pharmaceuticalpreparations normally contain about 0.5 to about 90% by weight of thecompounds of the formula (I) and/or their pharmaceutically acceptablesalts and/or their prodrugs. The amount of the active ingredient of theformula (I) and/or its pharmaceutically acceptable salts and/or itsprodrugs in the pharmaceutical preparations normally is from about 0.5to about 1000 mg, preferably from about 1 to about 500 mg.

In addition to the active ingredients of the formula (I) and/or theirpharmaceutically acceptable salts and to carrier substances, thepharmaceutical preparations can contain one or more additives such as,for example, fillers, disintegrants, binders, lubricants, wettingagents, stabilizers, emulsifiers, preservatives, sweeteners, colorants,flavorings, aromatizers, thickeners, diluents, buffer substances,solvents, solubilizers, agents for achieving a depot effect, salts foraltering the osmotic pressure, coating agents or antioxidants. They canalso contain two or more compounds of the formula (I) and/or theirpharmaceutically acceptable salts. In case a pharmaceutical preparationcontains two or more compounds of the formula (I) the selection of theindividual compounds can aim at a specific overall pharmacologicalprofile of the pharmaceutical preparation. For example, a highly potentcompound with a shorter duration of action may be combined with along-acting compound of lower potency. The flexibility permitted withrespect to the choice of substituents in the compounds of the formula(I) allows a great deal of control over the biological andphysico-chemical properties of the compounds and thus allows theselection of such desired compounds. Furthermore, in addition to atleast one compound of the formula (I) and/or its pharmaceuticallyacceptable salts, the pharmaceutical preparations can also contain oneor more other therapeutically or prophylactically active ingredients.

When using the compounds of the formula (I) the dose can vary withinwide limits and, as is customary and is known to the physician, is to besuited to the individual conditions in each individual case. It depends,for example, on the specific compound employed, on the nature andseverity of the disease to be treated, on the mode and the schedule ofadministration, or on whether an acute or chronic condition is treatedor whether prophylaxis is carried out. An appropriate dosage can beestablished using clinical approaches well known in the medical art. Ingeneral, the daily dose for achieving the desired results in an adultweighing about 75 kg is from about 0.01 to about 100 mg/kg, preferablyfrom about 0.1 to about 50 mg/kg, in particular from about 0.1 to about10 mg/kg, (in each case in mg per kg of body weight). The daily dose canbe divided, in particular in the case of the administration ofrelatively large amounts, into several, for example 2, 3 or 4, partadministrations. As usual, depending on individual behavior it may benecessary to deviate upwards or downwards from the daily dose indicated.

Furthermore, the compounds of the formula (I) can be used as synthesisintermediates for the preparation of other compounds, in particular ofother pharmaceutical active ingredients, which are obtainable from thecompounds of the formula I, for example by introduction of substituentsor modification of functional groups.

Compounds of formula (I) may be made in the following manner:

Compounds of the general formula (I) can be assembled from a suitablysubstituted isoquinoline moiety and a suitably substituted cycloalkylamine moiety.

Isoquinolines and isoquinolones like (i) or (ii), bearing a usefulresidue for coupling in 6-position, can be obtained by a wide variety ofmethods, for example reviewed in Alvarez et al. Science of Synthesis2005, 15, 661-838 and 839-906 and references cited therein.Isoquinolines can also be converted to isoquinolones by methodsdescribed in the literature e.g. WO 2007/012421 or WO 2007/012422, likeconversion of a suitable isoquinoline into the corresponding N-oxidewith an oxidating agent like hydrogen peroxide or metachloro perbenzoicacid and subsequent conversion into the corresponding 1-chloroderivative by a chlorinating agent like phosphorous oxy chloride,followed by displacement of the chlorine by an alcohol under basiccondition like sodium methoxide in methanol or conversion into thecorresponding 2H-isoquinolone by for example treatment with ammoniumacetate in acetic acid at elevated temperature. Also the N-oxide can bedirectly converted into the corresponding 1-alkoxy derivative byreacting it with a suitable chloroformiate in an alcoholic solvent likemethanol in presence of a base like triethylamine. It is understood,that the hydroxyl-group in 6-position of (ii) can be liberated at asuitable stage of the synthesis e.g. from treatment of a corresponding6-methoxy derivative with lewis acids like aluminium chloride or borontribromide. It is furthermore understood, that 2H-isoquinolones can beconverted into suitably protected 1-alkoxy isoquinolones by a variety ofmethods e.g. treatment of the corresponding 2H-isoquinolones withalkylating agents like benzyl bromide or methyl iodide in the presenceof a suitable base like silver carbonate or triethyl amine in a suitablesolvent like toluene or THF, or conversion of the said 2H-isoquinolonesinto their 1-chloro derivatives by treatment with a chlorinating agentlike phosphorous oxychloride, followed by displacement of the chlorineby an alcohol e.g. under basic conditions like sodium methoxide inmethanol. It is understood, that residues R₃, R₄, R₅, R₇, and/or R₈ caneither be incorporated in the starting materials for the synthesis ofthe respective isoquinoline or isoquinolone or can be introduced at asuitable later stage e.g. by halogenation like bromination orchlorination and subsequent replacement of said halogen by methods wellprecedented in the literature like for example Suzuki or HartwigBuchwald couplings using appropriate catalysts and coupling partnerslike boronic acids, amines or anilines.

One possible synthesis for a cycloalkyl amine substituted isoquinolinone(v) with L=O is described below in an exemplary fashion, but does notlimit the present invention. The cycloalkyl amine substitutedisoquinolinones (for example compound v) can be synthesized via avariety of methods. The following general scheme 1 illustrates some ofthe possible ways to access the isoquinolinones, but does not limit thepresent invention.

6-Fluoro-isoquinolones (i), for example substituted by R₃, R₄, R₅, R₇,and/or R₈ being for instance independently from each other substituentslike hydrogen, alkyl, alkoxy or halide, can be reacted with suitableR₁₃/R₁₄ substituted amino alcohols wherein R₁₃/R₁₄ are independentlyfrom each other for example hydrogen, alkyl or a protecting group likefor example Boc or Cbz in the presence of base such as DBU, cesiumcarbonate, or sodium hydride at temperatures ranging from ambient to100° C. to give the corresponding derivatives (iv). Optionally, thisconversion can already be performed at earlier stages of the synthesis(e.g. by reacting a suitable intermediate). It is understood, that thismay require in case of unprotected isoquinolones protection on thenitrogen or oxygen of the isoquinolone moiety by suitable methods, likereaction with suitably substituted alkyl or benzyl halides in thepresence of base.

Alternatively, the amino alcohols can be coupled to6-hydroxy-isoquinolones, such as (ii), under inversion of the hydroxylbearing carbon center of compounds like (iii), either protected with asuitable protecting group Q or unprotected, via a Mitsunobu reactionusing triphenylphosphine and dialkylazodicarboxylates such asdiethylazodicarboxylate or diisopropylazodicarboxylate in a suitablesolvent like tetrahydrofuran, or toluene. The products like (iv)obtained via these methods can then either be liberated to givecompounds of type (v) or, if a suitable amino functionality is present,be reacted with suitable aldehydes or ketones in the presence of areducing agent like sodium triacetoxy borohydride, sodium borohydride orsodium cyanoborohydride in a suitable solvent and in the presence of awater withdrawing agent like molecular sieves or a suitable ortho ester.This amino group may have to be liberated in an initial step, like forexample acidic removal of Boc-groups. Furthermore an amino group can beacylated by reacting it with a suitable acid chloride in the presence ofa base like triethyl amine or Hünig's base or by reacting it with asuitable carboxylic acid in the presence of a base like triethylamine orHünig's base and a coupling reagent like EDC, PyBOP or TOTU.

In case of use of protected isoquinolones, cleavage of the usedprotection groups is required to liberate the desired isoquinolone (v).This liberation, however, can be performed before or after the reductiveamination step, depending on the nature of the used aldehyde/ketone andthe protection group used.

Isoquinolone derivatives like (v) can be obtained as free bases or asvarious salts like for example hydrochlorides, hydrobromides,phosphates, trifluoroacetates, sulfates or fumarates. The salts obtainedcan be converted into the corresponding free base by either subjectingthem to ion exchange chromatography or for example by alkaline aqueoustreatment and subsequent extraction with suitable organic solvents likefor example methyl tert. butyl ether, chloroform, ethyl acetate orisopropanol/dichloromethane mixtures and subsequent evaporation todryness.

The cycloalkyl amine moieties like for example (iii) can by synthesizedvia a variety of methods. The following general schemes illustrate someof the possible ways to access the amines, but do not limit the presentinvention. It is within the abilities of a person skilled in the art toreplace the exemplary compounds shown in the schemes and exemplaryreagent given in the text by appropriate alternative compounds orreagents or to omit or add synthetic steps when appropriate.

The synthesis of a cycloalkyl aminoalcohol (iii) is described exemplaryin schemes 2 and 3 but does not limit the scope of substituents in thepresent invention. A cycloalkyl amine moiety (iii) with a secondary ortertiary amine subunit can for example be accessed starting from asuitably substituted cycloalkylnitrile (vi), which can be substitutedwith functionalities as alkyl, alkoxy, or acetals. To introduce anresidue R₁₀, if wanted, the nitrile can get functionalized inalpha-position by reaction with suitable electrophiles like described inthe literature (Organic Process Research & Development, 5(6), 587-592;2001), using for example a suitable fluorinated aryl compound and asuitable base like KHMDS, LiHMDS or sodium hydride in an inert solventlike toluene. Alternatively, a suitable nucleophile like aryl lithiumreagents can be reacted with a suitable ketone (xvi) to give thecorresponding alcohol, which can be converted into the correspondingnitrile (vii) by treatment with reagents like TMSCN.

Another option is construction of the cycloalkyl moiety for example byDieckmann condensations like described in the literature (Lednicer etal, J. Med. Chem. 1980, 23(4), 424-30; DeGraffenreid et al., J. Org.Chem. 2007, 72(19), 7455-7458) to give ketones like (xii), that can beconverted into their acetals (vii) by treatment with diols like ethylenediol, or can be directely converted into the corresponding alcoholsusing suitable reductive agents like sodium borohydride in a suitablesolvent like methanol, ethanol or THF. The obtained nitrile can then befor example further converted as described in schemes 2 and 4.

The functionalized nitrile (vii or xvii) can then for example bedirectly reacted with suitable nucleophiles for the introduction offunctional groups R₁₁ and R₁₂, for example lithium organyls or Grignardreagents to give compounds like (viii or iii). A suitable N-protectinggroup like t-butyloxycarbonyl or benzyloxycarbonyl may or may not beattached after this step depending on the nature of the starting nitrileand the complexity of the reactions to follow. For R₁₁═R₁₂, lithiumorganyls can be used as nucleophiles activated by addition of lewisacids like titanium isopropoxylate and cerium chloride.

For R₁₁ is H, the intermediate imine formed on addition of thenucleophiles can be isolated and reduced by suitable reductive agentslike cyanoborohydrides or borohydrides in solvents such astetrahydrofuran or alcohols. Alternatively, the nitrile (vii) can bereduced to the aldehyde (x) by suitable hydride donor reagents likediisobutylaluminiumhydride in cold organic solvents such as diethyletheror toluene and converted to appropriate imines (xi) like benzylimines orN-tert-butanesulfinyl imines via a lewis acid catalysed reaction withsuitably functionalized amines. These imines (xi) can then be reactedwith suitable nucleophilic reagents like lithium organyls, Grignardreagents or trimethylsilanes in combination with tetraalkyl fluorides tointroduce a variety of substituents like alkyl, cycloalkyl orheterocyclyl groups. The keto functionality can then be liberated bymethods known to the person skilled in art, for example by treatmentwith aqueous acids like acetic acid or hydrochloric acid in acetonemixtures, and subsequently reduced to the corresponding alcohols (iii),generally as cis/trans mixtures, by suitable reducing agents likeborohydrides in alcohols, tetrahydrofuran or toluene at deeptemperatures.

This liberation, however, can also be performed after the nitrilefunctionalization step (Scheme 4), depending on the nature of the usednitrile and the substitution pattern. If the ketone is reduced beforethe nitrile gets functionalized, generally only one isomer (cis ortrans) is obtained in high selectivity. For the conversion of nitrilesfrom type (xiii) to the amines (iii) the use of a suitable protectinggroup on the alcohol functionality may prove beneficial. Suitableprotecting groups are known to the person skilled in art and may beethers, like tetrahydropyrane, methoxymethyl or silyl ethers.

To obtain cycloalkyl amino moieties other than cycloalkyl aminoalcohols,various methods can be applied. The following general scheme (scheme 4)illustrates some of the possible ways to access these amines, but doesnot limit the present invention.

For instance, the hydroxy functionality of a compound (iii) can beconverted to a thiol via a Mitsunobu reaction using thioacetate andsubsequent basic cleavage with a suitable base, leading to aminomoieties of type (xiv). These thiols can—after coupling to suitableisoquinolinones under useful reaction conditions like for example in asimilar fashion as described above in scheme 1 for the coupling of(iii)—then be used to obtain compounds of formula (I) with the linkerunit L=S—or optionally be oxidized via methods known to the personskilled in the art to the corresponding sulfoxides and sulfones (forobtaining compounds of formula (I) with the linker unit L=SO and SO₂).The corresponding amines can be accessed via a reductive amination stepstarting from ketones such as compound (ix or xii) using suitable aminesin the presence of a reducing agent like sodium triacetoxy borohydride,sodium borohydride or sodium cyanoborohydride in the presence of a waterwithdrawing agent like molecular sieves or a suitable ortho ester.

In general, protective groups that may still be present in the productsobtained in the coupling reaction are then removed by standardprocedures. For example, tert-butyl protecting groups, in particular atert-butoxycarbonyl group which is a protection form of an amino group,can be deprotected, i.e. converted into the amino group, by treatmentwith trifluoroacetic acid. As already explained, after the couplingreaction also functional groups can be generated from suitable precursorgroups. In addition, a conversion into a pharmaceutically acceptablesalt or a prodrug of a compound of the formula (I) can then be carriedout by known processes.

In general, a reaction mixture containing a final compound of theformula (I) or an intermediate is worked up and, if desired, the productis then purified by customary processes known to those skilled in theart. For example, a synthesized compound can be purified using wellknown methods such as crystallization, chromatography or reversephase-high performance liquid chromatography (RP-HPLC) or other methodsof separation based, for example, on the size, charge or hydrophobicityof the compound. Similarly, well known methods such as NMR, IR and massspectrometry (MS) can be used for characterizing a compound of theinvention.

EXAMPLES

The following examples illustrate the various embodiments of the presentinvention and are part of the present invention.

Cis and trans nomenclature in the title of the respective compoundsrefer to the relative configuration of the —[CR₁₁R₁₂]_(r)NR₁₃R₁₄ residueand the L-residue at the cycloalkyl ring. This convention is maintainedfor the respective precursors.

cis-4-Hydroxy-1-phenylcyclohexanecarbonitrile (1)

To a suspension of 4-cyano-4-phenylcyclohexanone (25 g, 125 mmol) inabsolute ethanol (1 L) was added sodium borohydride (9.5 g, 251 mmol)portionwise over 30 minutes. The resulting mixture was stirred at roomtemperature for 2 hours, ice was then added and the crude mixturestirred for another hour. Ethanol was evaporated under reduced pressure,and the resulting aqueous layer was extracted with dichloromethane. Theorganic layer was dried over sodium sulphate, filtered and concentratedunder reduced pressure. The crude productcis-4-hydroxy-1-phenylcyclohexanecarbonitrile (25 g, containing approx.10% of the trans isomer) was used in the next step without any furtherpurification. R_(t)=3.99 min (Method 8). Detected mass: 202 (M+H⁺).

cis-4-Cyano-4-phenylcyclohexyl acetate (2)

To a solution of cis-4-hydroxy-1-phenylcyclohexanecarbonitrile (1, 0.2g, 1 mmol) in anhydrous pyridine (10 mL) were added acetic anhydride(0.1 mL, 1.2 mmol) and 4-dimethylaminopyridine (0.024 g, 0.2 mmol). Thereaction mixture was stirred at room temperature for 12 hours, and thenevaporated to dryness. A saturated aqueous solution of sodiumbicarbonate was added to the crude product and the mixture was extractedwith dichloromethane. The organic layer was dried over sodium sulphate,filtered and evaporated to dryness. The crude product was purified bysilica gel chromatography (eluting with 0 to 40% ethyl acetate incyclohexane) to give 3.39 g of cis-4-cyano-4-phenylcyclohexyl acetate(containing approx. 10% of trans isomer). R_(t)=7.34 min (Method 9).Detected mass: 266 (M+Na⁺).

cis-4-(1-Aminocyclopropyl)-4-phenylcyclohexyl acetate (3)

A 250-mL three necked round bottom flask equipped with a temperatureprobe and an argon line was charged with cis-4-cyano-4-phenylcyclohexylacetate (2, 3.39 g, 13.9 mmol) and anhydrous tetrahydrofuran (140 mL).The resulting solution was cooled to −75° C. and titanium (IV)isopropoxide (4.5 mL, 15.3 mmol) was added dropwise while the reactiontemperature remained below −70° C. Once the addition was completed,ethylmagnesium bromide (3M in diethyl ether) (10.2 mL, 30.6 mmol) wasadded dropwise. The mixture was stirred at −70° C. for 10 minutes andthen allowed to slowly warm to room temperature, while stirring wascontinued for another 30 minutes. At this stage, boron trifluorideetherate (3.5 mL, 28 mmol) was added, and stirring was continued for 1hour. Water (14 mL) was added, followed by 10% aqueous HCl (140 mL) anddiethyl ether (100 mL). A 10% aq. NaOH solution was added to theresulting clear mixture until the pH became basic. The product wasextracted with diethyl ether. The combined organic extracts were driedover anhydrous sodium sulphate. After evaporation of the solvent, theproduct was purified by flash chromatography on silica gel (eluting with0 to 100% ethyl acetate in cyclohexane) to yield 0.65 g ofcis-4-(1-aminocyclopropyl)-4-phenylcyclohexyl acetate. R_(t)=2.72 min(Method 7). Detected mass: 274 (M+H⁺).

cis-4-(1-Aminocyclopropyl)-4-phenylcyclohexanol (4)

To a solution of cis-4-(1-aminocyclopropyl)-4-phenylcyclohexyl acetate(3, 0.54 g, 2 mmol) in anhydrous methanol (20 mL) was added sodiummethoxide (0.5 N in methanol) (8.7 mL, 4.3 mmol). After stirring for 72hours at room temperature, the reaction mixture was cooled to 0° C., a1M solution of hydrochloric acid in diethyl ether (10 mL) was added, andthe resulting white precipitate was filtered off. The filtrate wasconcentrated under reduced pressure, and the resulting crude product wastriturated with a methanol/diethyl ether mixture. The beige solid wasisolated by filtration to give 400 mg ofcis-4-(1-aminocyclopropyl)-4-phenylcyclohexanol as the hydrochloride.R_(t)=2.33 min (Method 8). Detected mass: 232 (M+H⁺).

cis-4-(1-Aminocyclopropyl)-4-(2-fluorophenyl)cyclohexanol (5)

Utilizing the procedures described for the synthesis of 4, 0.219 g ofcis-4-(1-aminocyclopropyl)-4-(2-fluorophenyl)cyclohexanol (5) wasobtained as the hydrochloride (contaminated with 4% of trans isomer)starting from 4-cyano-4-(2-fluorophenyl)cyclohexanone. R_(t)=0.66 min(Method 7). Detected mass: 250 (M+H⁺).

cis-4-(1-Aminopropyl)-4-phenylcyclohexanol (6)

To a solution of cis-4-hydroxy-1-phenylcyclohexanecarbonitrile (1, 1.0g, 4.97 mmol) in anhydrous toluene (100 mL) was added dropwise asolution of ethylmagnesium bromide (3M in diethyl ether, 10 mL, 30mmol). The reaction mixture was refluxed overnight, then poured ontoice. The resulting mixture was extracted with diethyl ether, the organiclayer was dried over sodium sulphate, filtered and concentrated underreduced pressure. To a solution of this crude product in absoluteethanol (100 mL) was added sodium borohydride (0.257 g, 7.5 mmol). Thereaction mixture was stirred at room temperature for 2 hours, aqueous 1NHCl was then added until pH=1.3. Ethanol was evaporated under reducedpressure, the resulting aqueous phase was washed with diethyl ether,then neutralized with a saturated aqueous sodium bicarbonate solutionand eventually extracted with diethyl ether and chloroform,subsequently. The combined organic layers were dried over anhydroussodium sulphate, filtered and evaporated to dryness. The crude productwas dissolved in 15 mL of methanol and HCl (4N in dioxane) (0.9 mL) wasadded dropwise. The suspension was stirred for 30 min, then evaporatedto dryness to yield 0.858 g ofcis-4-(1-aminopropyl)-4-phenylcyclohexanol (6) as the hydrochloride(contaminated with 10% of trans isomer). R_(t)=2.59 min (Method 8).Detected mass: 234 (M+H⁺).

cis-4-(Methoxymethoxy)-1-phenylcyclohexanecarbonitrile (7)

A stirred solution of potassium tert-butoxide (1.6 M in tert-butanol,37.3 mL, 37.3 mmol) was cooled to 0° C. and anhydrous DMF (6 mL) wasadded before the mixture began to freeze. A solution ofcis-4-hydroxy-1-phenylcyclohexanecarbonitrile (1, 3 g, 14.9 mmol) inanhydrous DMF (30 mL) was added to the reaction mixture. A solution ofchloromethyl methyl ether (2.83 mL, 37.3 mmol) was then added dropwiseat 2-4° C. and the mixture was gradually allowed to warm to roomtemperature while stirring was continued overnight. The mixture waspoured onto cold aqueous sodium bicarbonate solution, then extractedwith diethyl ether. The organic layer was dried over sodium sulphate andevaporated. The crude product was purified by chromatography on silicagel to yield 2.2 g of the title compound. R_(t)=7.01 min (Method 9).Detected mass: 246 (M+H⁺)

cis-4-(1-Amino-1-methylethyl)-4-phenylcyclohexanol (8)

A suspension of commercial anhydrous cerium chloride (Alfa Aesar, 2 g,8.15 mmol) in anhydrous THF (12 mL) was heated to 45° C. for 3 h undervigourous stirring. The slurry was cooled to room temperature andtreated with cis-4-(methoxymethoxy)-1-phenylcyclohexanecarbonitrile (7,1 g, 4.08 mmol). After cooling to −10° C., a 1.5 M solution of MeLi.LiBr(6.79 mL, 10.2 mmol) in diethyl ether was added dropwise over 20minutes, then the resulting brown slurry was stirred for an additional20 min. The reaction was quenched by addition of concentrated NH₄OH (2.6mL) over 10 min. The yellow suspension obtained was allowed to warm toroom temperature, stirred for 30 min, diluted with THF and thenfiltered. The wet cake was rinsed several times with THF. The combinedfiltrates were then concentrated to almost dryness, diluted withdichloromethane and washed with 0.1 N NaOH. The organic layer was driedwith sodium sulphate and evaporated.

The crude mixture was suspended in a mixture of methanol (20 mL) andaqueous 2N HCl (20 mL) then stirred overnight at room temperature. Afterevaporation of methanol and filtration, the filtrate was concentrated todryness to yield 0.38 g of a crude mixture of the title compound (8).R_(t)=2.43 min (Method 9). Detected mass: 234 (M+H⁺).

6,7-difluoro-5-methyl-isoquinoline (43) a)[1-(3,4-Difluoro-2-methylphenyl)-methylidene]-2,2-dimethoxyamine (40)

3,4-difluoro-2-methylbenzaldehyde (26 g, 166 mmol) was dissolved intoluene (182 mL) and reacted with 2-aminoacetaldehyde dimethylacetal(19.3 g, 183 mmol) and toluene sulphonic acid (3.2 g) for 2 hours in aDean-Stark apparatus. The solution was allowed to cool down, extractedwith saturated sodium bicarbonate solution, water and brine, dried oversodium sulphate and evaporated to dryness to give 40.4 g of a darkyellow oil which was used without further purification.

b) 3,4-Difluoro-2-methylbenzyl-2,2-dimethoxyethylamine (41)

[1-(3,4-Difluoro-2-methylphenyl)-methylidene]-2,2-dimethoxyamine (40,40.4 g) was dissolved in ethanol (225 mL). Sodium borohydride (4.8 g,124 mmol) was added portionwise. Stirring was continued overnight. Forworkup, acetic acid was added until no gas evolution could be observed.Then the solution was evaporated to dryness, taken up in dichloromethaneand washed with saturated sodium bicarbonate solution and twice withwater. The organic layer was washed with brine, dried over magnesiumsulphate and evaporated to dryness. The crude product obtained (37.8 g)was used without purification.

c)N-(3,4-Difluoro-2-methylbenzyl)-N-(2,2-dimethoxyethyl)-4-methylphenyl-sulphonylamine(42)

3,4-Difluoro-2-methylbenzyl-2,2-dimethoxyethylamine (41, 37.8 g) wasdissolved in dichloromethane (100 mL). Pyridine (42 mL) was added. At 0°C. a solution of p-toluenesulphonyl chloride (36.8 g, 193 mmol) indichloromethane was added dropwise. The reaction was allowed to warm toroom temperature and stirring continued until conversion was complete.For workup, the reaction mixture was diluted with dichloromethane (100mL) and extracted twice with 1.5M hydrochloric acid, twice with sodiumbicarbonate solution and once with brine. The organic layer was driedover magnesium sulphate, evaporated to dryness to give crude product asan orange oil (68.3 g). This was used without further purification.

d) 6,7-difluoro-5-methyl-isoquinoline (43)

Aluminium trichloride (112 g, 838 mmol) was suspended in dichloromethane(250 mL) at 0° C. A solution ofN-(3,4-difluoro-2-methylbenzyl)-N-(2,2-dimethoxyethyl)-4-methylphenyl-sulphonylamine(42, 68.3 g) in dichloromethane (250 mL) was added. The reaction mixturewas heated at 50° C. for 2 hours, before being cooled to 0° C. andpoured on ice. The organic layer was separated, and the aqueous layerextracted twice more with dichloromethane/isopropanol (3:1). Thecombined organic phase was extracted twice with saturated sodiumbicarbonate solution and dried over magnesium sulphate, beforefiltration and evaporation gave 63.5 g of crude dark brown semi-solidproduct. This was purified by chromatography on silica gel. Elution withethyl acetate/heptane (5%:95% to 35%:65%) gave 11.3 g of the titlecompound 43 as a tan-coloured solid. R_(t)=0.86 min (Method 10).Detected mass: 180.1 (M+H⁺).

The Isoquinolines in the following table were obtained by following asimilar reaction sequence as used for synthesis of 43.

Comp. Starting Chemical R_(t)/ No. compound Product Name [M + H⁺] [min]Method 44 3,5-dimethyl- 4-fluoro- benzaldehyde

5,7-dimethyl- 6-fluoro- isoquinoline 176.1 1.06 10 45 3,4-difluoro-benzaldehyde

6,7-difluoro- isoquinoline 166.1 1.07 2 46 3-bromo-4- fluoro-benzaldehyde

7-bromo-6- fluoro- isoquinoline 226.0 228.3 0.91 4 47 4-fluoro-3-methoxy- benzaldehyde

6-fluoro-7- methoxy- isoquinoline 178.1 0.90 10 48 4-fluoro-3- methyl-benzaldehyde

6-fluoro-7- methyl- isoquinoline 161.9 0.90 10

7-Chloro-6-fluoro-isoquinoline 2-oxide (9)

50 g of 7-chloro-6-fluoro-isoquinoline (prepared according to WO2007/012422) were dissolved in dichloromethane and cooled to 5° C. 69.6g of m-chloro-perbenzoic acid (70%) were added portionwise. The mixturewas stirred at room temperature. When conversion was complete, themixture was diluted with 1.5 L of dichloromethane and washed three timeswith saturated sodium bicarbonate solution. The organic layer was driedover sodium sulphate and evaporated to dryness to give 47.6 g of thedesired product 9. R_(t)=0.98 min (Method 5). Detected mass: 198.1(M+H⁺).

7-Chloro-6-fluoro-1-methoxy-isoquinoline (10)

10 g of 7-Chloro-6-fluoro-isoquinoline 2-oxide (9) were dissolved in 100mL of dry methanol. 12 mL of ethyl chloroformate were added dropwise at−10° C. The mixture was allowed to stir for 15 minutes and then 28 mL oftriethylamine, dissolved in 55 mL of methanol, were added dropwise at−20° C. over 1 h.

100 mL of 2N aqueous sodium hydroxide solution were added and the formedprecipitate was filtered. Additional product was precipitated byaddition of 2N sodium hydroxide solution and water to the mother liquor.The combined solids were dried to give 7.8 g of the desired product(10). R_(t)=3.75 min (Method 1). Detected mass: 212.0 (M+H⁺).

The following compounds were obtained in a similar fashion as describedfor the synthesis of 10, starting from the respective isoquinolines.

Comp. Starting R_(t)/ No. compound Product Chemical Name [M + H⁺] [min]Method 49 5-Chloro-6- fluoro- isoquinoline

5-Chloro-6-fluoro- 1-methoxy-iso- quinoline 212.0 1.78 10 50 45

6,7-difluoro-1- methoxy-iso- quinoline 196.1 3.53 1 51 43

6,7-Difluoro-1- methoxy-5- methyl- isoquinoline 210.1 3.85 2 52 48

6-fluoro-1- methoxy-7- methyl-iso- quinoline 192.1 3.44 2 53 44

6-Fluoro-1- methoxy-5,7- dimethyl-iso quinoline 206.1 3.74 2 54 47

6-Fluoro-1,7- dimethoxy- isoquinoline 208.1 3.1 2

1-Benzyloxy-7-chloro-6-fluoro-isoquinoline (38)

7-Chloro-6-fluoro-2H-isoquinolin-1-one (prepared according to WO2007/012422; 52.2 g) was dissolved in THF (1 L). After addition ofsilver carbonate (145.5 g) and benzyl bromide (40.6 mL), the mixture wasstirred at room temperature overnight. Another 6.2 mL of benzyl bromidewere added and the mixture was stirred at 70° C. for 2 h. After coolingdown to room temperature, the reaction mixture was diluted by additionof 1 L of ethyl acetate and filtered over celite. The filter cake waswashed thoroughly, the organic layer was evaporated and subjected tosilica gel chromatography (n-heptanes: methyl tert. butyl ether) to give27.8 g of the title compound (38). R_(t)=3.73 min (Method 1). Detectedmass: 288.1 (M+H⁺).

1-Benzyloxy-4-benzyl-7-chloro-6-fluoro-isoquinoline (55)

As a side product of the preparation of1-benzyloxy-7-chloro-6-fluoro-isoquinoline (38), 8.45 g of1-benzyloxy-4-benzyl-7-chloro-6-fluoro-isoquinoline (55) could beisolated by silica gel chromatography. R_(t)=4.04 min (Method 1).Detected mass: 378.1 (M+H⁺).

1-Benzyloxy-7-methyl-6-fluoro-isoquinoline (39)

1-Benzyloxy-7-methyl-6-fluoro-isoquinoline (39) has been preparedaccording to the procedure described for the synthesis of (38) startingfrom 7-methyl-6-fluoro-2H-isoquinolin-1-one (prepared according to theprotocol described in WO 2007/012421 or WO 2007/012422). R_(t)=4.00 min(Method 1). Detected mass: 268.1 (M+H⁺).

1-(4-Fluoro-phenyl)-4-oxo-cyclohexanecarbonitrile (12) a)5-Cyano-5-(4-fluoro-phenyl)-2-oxo-cyclohexanecarboxylic acid methylester (11)

70 mL of methylacrylate and 50 g of 4-fluorophenylacetonitrile weredissolved in a mixture of 200 mL of THF and 50 mL of dry methanol. 150mL of sodium methylate (30% in methanol) were added dropwise, whiletemperature was maintained below 40° C. The mixture was stirred at roomtemperature for 15 h and heated for another 4 h at 50° C. When thereaction was complete, the mixture was allowed to cool to roomtemperature and poured onto a cold 2N aqueous hydrochloric acidsolution. The aqueous layer was extracted three times with ethyl acetateand the combined organic layer was washed with water and brine, driedover magnesium sulphate and evaporated to give 101.5 g of the desiredproduct. R_(t)=1.59 min (Method 5). Detected mass: 276.2 (M+H⁺).

b) 1-(4-Fluoro-phenyl)-4-oxo-cyclohexanecarbonitrile (12)

101.5 g of 5-Cyano-5-(4-fluoro-phenyl)-2-oxo-cyclohexanecarboxylic acidmethyl ester (11) were dissolved in 680 mL of ethanol and 171 mL ofconcentrated aqueous hydrochloric acid were added. The mixture washeated to reflux for 40 h, then evaporated. The residue was taken up inwater and extracted with dichloromethane. The organic layer was washedwith brine, dried over magnesium sulphate and evaporated to give 95.2 gof crude product, that was purified by silica gel filtration(heptanes:ethyl acetate) to yield 50.4 g of the desired product 12.R_(t)=1.26 min (Method 1). Detected mass: 218.2 (M+H⁺).

1-(4-Methoxy-phenyl)-4-oxo-cyclohexanecarbonitrile (56)

56 was obtained from methylacrylate and 4-methoxyphenylacetonitrile in asimilar fashion as described for synthesis of (12). R_(t)=4.24 min(Method 3). Detected mass: 230.1 (M+H⁺).

1-Cyano-1-(3-fluorophenyl)cyclohexan-4-one (58) a)1-Cyano-1-(3-fluorophenyl)-3-methoxycarbonylcyclohexan-4-one (57)

Potassium t-butoxide (62.3 g, 555 mmol) was added dropwise to a solutionof 3-fluorophenylacetonitrile (56, 25 g, 185 mmol) in THF (500 mL). Thereaction mixture was stirred overnight. The reaction mixture wasacidified with hydrochloric acid (3M) and extracted withdichloromethane. The organic extracts were evaporated to yield 57.2 g ofan orange oil. R_(t)=3.39 min (Method 3). Detected mass: 275.1 (M+H⁺).

b) 1-Cyano-1-(3-fluorophenyl)cyclohexan-4-one (58)

A mixture of1-cyano-1-(3-fluorophenyl)-3-methoxycarbonylcyclohexan-4-one (57, 51 g,185 mmol), water (54.8 mL) and DMSO (840 mL) was heated and stirred at150° C. for 3 hours, followed by stirring at room temperature overnight.The reaction mixture was evaporated and purified by chromatography onsilica gel. Elution with ethyl acetate/heptane (5%:95% to 30%:70%) gave28 g of desired material as a solid product. R_(t)=3.89 min (Method 3).Detected mass: 218.2 (M+H⁺).

The following cyclohexanones were prepared using the same procedure asdescribed for 58, starting from the respective phenylacetonitrils.

Comp. Starting Chemical R_(t)/ No. compound Product Name [M + H⁺] [min]Method 59 4-bromo-phenyl acetonitrile

1-cyano-1-(4- bromophenyl) cyclo-hexan- 4-one 277.9 4.79 3 602-chloro-phenyl acetonitrile

1-cyano-1-(2- chlorophenyl) cyclo-hexan- 4-one 275.2 (M + CH₃CN + H⁺)1.87 4 61 3-methoxy- phenyl acetonitrile

1-cyano-1-(3- methoxyphen yl)cyclo- hexan-4-one 229.1 4.31 6 624-isopropyl- phenyl acetonitrile

1-cyano-1-(4- isopropylphenyl) cyclo- hexan-4-one 285.3 (M + CH₃CN + H⁺)2.23 4 63 2-methoxy- phenyl acetonitrile

1-cyano-1-(2- methoxyphenyl) cyclo- hexan-4-one 230.2 3.81 6 642-fluoro-phenyl acetonitrile

1-cyano-1-(2- fluorophenyl) cyclohexan-4- one 259.3 (M + CH₃CN + H⁺)1.79 4

1-Cyano-1-(2,4-difluorophenyl)cyclohexanone (65)

Potassium t-butoxide (55 g, 489 mmol) was added to a stirred solution of2,4-difluorophenylacetonitrile (25 g, 163 mmol) and methyl acrylate(28.1 g, 29.4 mL, 326 mmol) in THF (475 mL) at room temperature. Afterone hour stirring, water (2.4 L) was added and the mixture stirred for 2hours at 68° C. After cooling the mixture was extracted with methyl tertbutyl ether. After drying over sodium sulphate the organic phase wasevaporated to give 34.7 g of an orange oil which was purified bychromatography on silica gel. Elution with ethyl acetate/heptane (5%:95%to 35%:65%) gave the desired product after evaporation as 19 g of acolourless crystalline solid. R_(t)=3.84 min (Method 3). Detected mass:236.3 (M+H⁺).

The following cyclohexanones were prepared using the same procedure asdescribed for 65, starting from the respective phenylacetonitrils:

Comp. Starting R_(t)/ No. compound Product Chemical Name [M + H⁺] [min]Method 66 3-bromo- phenyl acetonitrile

1-cyano-1-(3- bromophenyl) cyclohexan-4-one 278.1 4.26 18 67 2-bromo-phenyl acetonitrile

1-cyano-1-(2- bromophenyl) cyclohexan-4-one 302.2 (M + Na⁺) 4.45 6 68Pyrid-2-yl acetonitrile

1-cyano-1- (pyrid-2-yl) cyclohexan-4-one 201.1 1.75 1 69 4-fluor-2-methylphenyl acetonitrile

1-cyano-1-(4- fluoro-2- methylphenyl) cyclohexan-4- one 232.3 4.02 6 703,5-difluoro- phenyl acetonitrile

1-cyano-1-(3,5- difluorophenyl) cyclohexan-4- one 236.1 4.02 6 713,4-difluoro- phenyl acetonitrile

1-cyano-1-(3,4- difluorophenyl) cyclohexan-4- one 236.2 3.98 6 722-methyl phenyl acetonitrile

1-cyano-1-(2- methylphenyl) cyclohexan-4- one 214.3 3.92 6 732-trifluoro methoxy phenyl acetonitrile

1-cyano-1-(2- trifluoromethoxy- phenyl)cyclo- hexan-4-one 284.1 2.26 2074 4-fluoro-3- methoxy phenyl acetonitrile

1-cyano-1-(4- fluoro-3- methoxy- phenyl) cyclohexan-4-one 248.2 3.89 675 3-ethoxy phenyl acetonitrile

1-cyano-1-(3- ethoxyphenyl) cyclohexan-4- one 244.3 4.19 6 763-methoxy-4- methylphenyl acetonitrile

1-cyano-1-(3- methoxy-4- methylphenyl) cyclohexan-4- one 244.0 4.53 6 774-trifluoro methoxy phenyl acetonitrile

1-cyano-1-(4- trifluoromethoxy- phenyl) cyclohexan-4- one 284.2 4.36 6

cis-4-Hydroxy-1-(4-fluoro-phenyl)cyclohexanecarbonitrile (13)

20 g of 1-(4-Fluoro-phenyl)-4-oxo-cyclohexanecarbonitrile (12) weredissolved in 300 mL of dry ethanol and cooled to −20° C. 3.83 g ofsodium borohydride were added and the mixture was allowed to slowly warmto room temperature. When conversion was complete, 150 mL of water wereadded and the pH was adjusted to 2 by addition of 2N hydrochloric acid.The mixture was extracted with ethyl acetate three times and thecombined organic layer was extracted with brine, dried over magnesiumsuphate and evaporated to dryness. The resulting residue wascrystallized from n-heptanes:ethyl acetate to give 11.9 g of the desiredproduct. R_(t)=2.78 min (Method 1). Detected mass: 220.1 (M+H⁺).

cis-4-(tert-Butyl-dimethyl-silanyloxy)-1-(4-fluoro-phenyl)-cyclohexane-carbonitrile(78)

30 g of cis-4-Hydroxy-1-(4-fluoro-phenyl)-cyclohexanecarbonitrile (13)were dissolved in 350 mL of dry dichloromethane. 39.8 mL of 2,6-lutidinewere added and the mixture was cooled to 0° C. 37.7 mL oftert.-butyldimethylsilyl trifluoromethansulfonate were added and themixture was stirred at room temperature overnight. The reaction mixturewas diluted with dichloromethane, extracted twice with water, 0.1Nhydrochloric acid and once with saturated sodium bicarbonate and brine,dried over magnesium sulphate, evaporated to dryness and purified bysilica gel chromatography to give 43.8 g of the desired product.R_(t)=3.21 min (Method 12). Detected mass: 334.2 (M+H⁺).

cis-4-(1-amino-propyl)-4-(4-fluoro-phenyl)cyclohexanol (14)

Under argon, 2 g ofcis-4-hydroxy-1-(4-fluoro-phenyl)cyclohexanecarbonitrile (13) weredissolved with cooling in a 1M solution of ethyl magnesium bromide inTHF (or diethyl ether, alternatively). The reaction mixture was refluxedfor 14 h, cooled to room temperature and diluted with 600 mL of THF. Themixture was quenched by addition of a minimal amount of methanol,filtered over celite and evaporated to dryness. The resulting foam wasdissolved in 300 mL of ethanol and 690 mg of sodium borohydride wereadded portionwise under cooling. The mixture was allowed to stir untilthe reaction was complete, evaporated to dryness and the resultingresidue was partitioned between 1N aqueous HCl and ethyl acetate. Theorganic layer was extracted once with 1N HCl and the combined aqueouslayers were washed with ethyl acetate and subsequently adjusted to pH 12by addition of 5N sodium hydroxide solution. The aqueous layer wasextracted twice with dichloromethane, the combined dichloromethanelayers were washed with brine, dried over sodium sulphate and evaporatedto give 1.72 g of the desired product. R_(t)=2.25 min (Method 1).Detected mass: 252.2 (M+H⁺).

Alternatively, 14 can be obtained employing 78 in a similar reaction:

18.3 g of 78 were dissolved in 183 mL of dry toluene and 36.6 mL of asolution of ethyl magnesium bromide (3M in diethylether) were added. Themixture was stirred at 80° C. for 16 h, diluted with THF, cooled to 5°C. and quenched by addition of a few mL of ethanol. The mixture wasfiltered over celite, the solution evaporated to dryness and the residuewas taken up in 100 mL of ethanol. 4.15 g of sodium borohydride wasadded portionwise and stirring was continued overnight. The mixture wasevaporated to dryness, the mixture was taken up in dichloromethane andextracted with 2N HCl and brine. The organic layer was evaporated, theresidue was taken up in methyl tert.butyl ether and extracted severaltimes with 2N HCl. The combined HCl layers were adjusted to pH 12 byaddition of 5N sodium hydroxide and extracted with dichloromethane. Thedichloromethane layer was dried over MgSO₄ and evaporated to give 13.0 gof the desired product.

cis-4-(1-Amino-1-methyl-ethyl)-4-(4-fluoro-phenyl)cyclohexanol (79)

300 mg of 78 were dissolved in 10 mL of dry diethyl ether. Then, 0.3 mLof methyl magnesium bromide (3M in diethyl ether) were added. Themixture was cooled to 0° C. and 0.85 mL of a solution of methyl lithium(1.6 M) were added. After 1 h, 255 mg of titanium(IV) isopropoxide wereadded. 10 minutes later 1.4 mL of a solution of methyl lithium (1.6 M)in diethylether were added. The mixture was stirred overnight. Then 5 mLof 2N sodium hydroxide were added slowly at 0° C., 30 mL of methyltert.butyl ether were added and the NaOH layer was extracted severaltimes with methyl tert.butyl ether. The combined organic layer was driedand evaporated. The resulting residue was dissolved in 5 mL of methyltert.butyl ether, cooled to 0° C. and 5 mL of 2N hydrochloric acid wereadded. Stirring was continued overnight, the ether layer was extractedagain with 2N hydrochloric acid and the combined aqueous layer wascooled to 0° C. and 4 mL of 5N sodium hydroxide solution were added. Theaqueous layer was extracted several times with dichloromethane, thecombined dichloromethane layers were dried and evaporated to give 80 mgof the desired product. R_(t)=2.33 min (Method 3). Detected mass: 217.2(M+H⁺)

8-(4-Fluoro-phenyl)-1,4-dioxa-spiro[4.5]decane-8-carbonitrile (15)

15 g of 1-(4-Fluoro-phenyl)-4-oxo-cyclohexanecarbonitrile (12) weredissolved in 500 mL of toluene, then 900 mg of p-toluene sulfonic acidwere added and the reaction mixture was heated in a Dean-Stark apparatusfor 6 h. The mixture was allowed to cool to room temperature and washedtwice with saturated aqueous sodium bicarbonate solution and brine,dried over magnesium sulphate and evaporated to dryness to yield 17.9 gof the desired product. R_(t)=1.47 min (Method 5). Detected mass: 262.2(M+H⁺).

{1-[8-(4-Fluoro-phenyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-butyl}-carbamicacid tert-butyl ester (16)

1.5 g of 8-(4-Fluoro-phenyl)-1,4-dioxa-spiro[4.5]decane-8-carbonitrile(15) were dissolved in 2.9 mL of a 2M solution of propylmagnesiumchloride in diethylether. The mixture was heated under reflux overnight.Another equivalent of propylmagnesium chloride solution was added andheating was continued for another day. The mixture was diluted bydiethyl ether (THF could be used alternatively) and a minimal amount ofsaturated sodium sulphate solution was added. The mixture was filteredover celite and the precipitate was washed with diethyl ether. 490 mg ofsodium borohydride was added to the combined organic layer and themixture was allowed to stir until conversion was complete. A mixture of2N HCl, brine and water (1:3:6) was added. The phases were separated,the organic layer was extracted twice with the mixture of 2N HCl, brineand water (1:3:6). The combined aqueous layer was adjusted to alkalinepH by addition of 2M sodium hydroxide solution and extracted twice withdichloromethane. The combined dichloromethane layer was washed withbrine, and dried over sodium sulphate.

5 mL of triethylamine and 5.86 g of di-tert.-butyl dicarbonate wereadded to the dichloromethane layer and the mixture was stirred at roomtemperature overnight. The mixture was washed with 1N sodium hydroxide,a mixture of 2N hydrochloric acid, brine and water (1:3:6) and brine,dried over sodium sulphate and evaporated to dryness. The crude productwas purified by silica gel chromatography (heptanes:ethyl acetate) togive 1.22 g of the desired product. R_(t)=5.18 min (Method 3). Detectedmass: 815.4 (2M+H⁺).

{1-[1-(4-Fluoro-phenyl)-4-oxo-cyclohexyl]-butyl}-carbamic acidtert-butyl ester (17)

1.22 g of{1-[8-(4-fluoro-phenyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-butyl}-carbamicacid tert-butyl ester (16) were dissolved in 42 mL of acetone and 3 mLof 1N hydrochloric acid were added. The mixture was stirred at roomtemperature until conversion was complete. 40 mL of saturated aqueoussodium bicarbonate solution were added and the reaction mixture wasextracted with ethyl acetate three times. The combined organic layer wasextracted with brine, dried over sodium sulphate and evaporated todryness to give 966 mg of crude (17), that was sufficiently pure forfurther conversion. R_(t)=1.72 min (Method 5). Detected mass: 308.2(M-Isobutene+H⁺).

trans-{1-[1-(4-Fluoro-phenyl)-4-hydroxy-cyclohexyl]-butyl}-carbamic acidtert-butyl ester (18)

0.97 g of {1-[1-(4-Fluoro-phenyl)-4-oxo-cyclohexyl]-butyl}-carbamic acidtert-butyl ester (17) were dissolved in 14 mL of ethanol and 119 mg ofsodium borohydride were added at −20° C. The mixture was allowed to warmto room temperature and stirred overnight. The mixture was evaporated,the residue was dissolved in ethyl acetate and washed twice with 2Nhydrochloric acid and once with brine. The organic layer was dried oversodium sulphate and evaporated to dryness to give the crude product,that was purified by silica gel chromatography (heptanes:ethyl acetate)to give 619 mg of (18). R_(t)=3.46 min (Method 1). Detected mass: 366.3(M+H⁺).

trans-4-(1-Amino-butyl)-4-(4-fluoro-phenyl)cyclohexanol (19)

619 mg oftrans-{1-[1-(4-Fluoro-phenyl)-4-hydroxy-cyclohexyl]-butyl}-carbamic acidtert-butyl ester (18) were dissolved in 2 mL of isopropanol and 2 mL of2N aqueous hydrochloric acid were added. The mixture was stirredovernight. Water was added and the isopropanol was removed in vacuo. Theresidue was taken up in water and lyophilized for another two times togive 1.64 g of (19) as the hydrochloride. R_(t)=2.27 min (Method 1).Detected mass: 266.2 (M+H⁺).

[1-Methyl-1-(4-oxo-cyclohexyl)-ethyl]-carbamic acid tert-butyl ester(20)

A suspension of commercial anhydrous cerium chloride (ABCR, 8.8 g) inanhydrous THF (62 mL) was heated for 4 h at 60° C. under vigourousstirring. The slurry was cooled to room temperature and treated with 3 gof 4-cyanocyclohexanone cyclic ethylene acetal. After cooling to −20°C., 35 mL of a 1.5 M solution of MeLi.LiBr in diethyl ether were addeddropwise. The mixture was allowed to stir for 1 h at −10° C., then 20 mLof THF were added and the reaction was quenched by addition ofconcentrated NH₄OH (10 mL) over 10 min. The mixture was allowed to warmto room temperature, stirred for 30 min, diluted with methyl tert. butylether and then filtered. The filter cake was rinsed several times withmethyl tert. butyl ether. The combined filtrates were then concentratedin vacuo.

The crude product was dissolved in dichloromethane and extracted twicewith 0.1N HCl. The combined HCl layers were washed with dichloromethane,cooled and the pH was adjusted to 12 by addition of 5 N sodium hydroxidesolution. The aqueous layer was extracted twice with dichloromethane.The dichloromethane layers were combined, washed with brine, and driedover sodium sulphate.

1.82 g of triethylamine and 2.74 g of di-tert.-butyl dicarbonate wereadded. The mixture was stirred for two days at room temperature, washedwith 1N sodium hydroxide solution, twice with 0.1 N hydrochloric acidand water, and once with brine, dried over sodium sulphate andevaporated to dryness to give 3.0 g of crude product.

The crude product was dissolved in 100 mL of acetone and 10 mL of 1N HClwere added and stirred at room temperature. Additional HCl was added andstirring was continued until conversion was complete. Sodium hydroxidesolution and methyl-tert.-butyl ether was added, the aqueous layer wasseparated and extracted with methyl-tert.-butyl ether. The combinedether layers were dried over sodium sulphate and evaporated to drynessto give 2.4 g of (20). R_(t)=3.08 min (Method 1). Detected mass: 256.2(M+H⁺).

[1-Methyl-1-(4-hydroxy-cyclohexyl)-ethyl]carbamic acid tert-butyl ester(21)

2.91 g of [1-Methyl-1-(4-oxo-cyclohexyl)-ethyl]-carbamic acid tert-butylester (20) were dissolved in 60 mL of ethanol and 473 mg of sodiumborohydride were added at −20° C. The mixture was allowed to warm toroom temperature and stirred for 3.5 h. The mixture was evaporated, theresidue was dissolved in ethyl acetate and washed twice with 2Nhydrochloric acid and once with brine. The organic layer was dried oversodium sulphate and evaporated to dryness to give 2.74 g of (21).R_(t)=1.27 min (Method 5). Detected mass: 194 (M-Isobutene-H₂O+H⁺).

4-(1-Amino-1-methyl-ethyl)-cyclohexanol (22)

580 mg of [1-Methyl-1-(4-hydroxy-cyclohexyl)-ethyl]-carbamic acidtert-butyl ester (21) were dissolved in 10 mL of isopropanol and 10 mLof 2N hydrochloric acid were added. The mixture was stirred overnight.Water was added and the isopropanol was removed in vacuo. The residuewas taken up in water and lyophilized for another two times from waterto give 515 mg of (22) as the hydrochloride. R_(t)=0.18 min (Method 5).Detected mass: 158.2 (M+H⁺).

Example 1cis-6-[4-(1-Amino-propyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-onea)cis-1-[4-(7-Chloro-1-methoxy-isoquinolin-6-yloxy)-1-(4-fluoro-phenyl)-cyclohexyl]-propylamine(23)

1.7 g of cis-4-(1-Amino-propyl)-4-(4-fluoro-phenyl)-cyclohexanol (14)were dissolved under argon in 50 mL of dry dimethyl acetamide. 513 mg ofsodium hydride (95%) were added portionwise under cooling and themixture was allowed to stir for 10 minutes. 1.57 g of7-Chloro-6-fluoro-1-methoxy-isoquinoline (10) were added and the mixturewas heated at 50° C. for 3 h. Stirring was continued overnight at roomtemperature. The reaction mixture was cooled in an ice bath and 50 mL ofwater were added carefully. The mixture was extracted four times withdichloromethane:isopropanol (3:1) and the combined organic layer waswashed three times with water and once with brine, dried over sodiumsulphate and evaporated to dryness. Water was added and the mixture waslyophilized. The crude product was subjected to silica gelchromatography (dichloromethane:methanol) to give 1.66 g of the desiredproduct. R_(t)=3.45 min (Method 1). Detected mass: 443.2 (M+H⁺).

b)cis-6-[4-(1-Amino-propyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one(Example 1)

1.66 g ofcis-1-[4-(7-Chloro-1-methoxy-isoquinolin-6-yloxy)-1-(4-fluoro-phenyl)-cyclohexyl]-propylamine(23) were dissolved in 16 mL of a mixture of isopropanol and 1Nhydrochloric acid (1:1) and heated in a microwave oven for 20 minutes at120° C. Water was added, the isopropanol removed in vacuo and theremaining solution was lyophilized. The residue was taken up in waterand lyophilized for another two times from water to give 1.64 g of thedesired product Example 1 as the hydrochloride. R_(t)=2.67 min (Method1). Detected mass: 429.2 (M+H⁺).

Example 2cis-6-[4-(1-Amino-cyclopropyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-onea)cis-1-[4-(1-Benzyloxy-7-chloro-isoquinolin-6-yloxy)-1-phenyl-cyclohexyl]-cyclopropylamine(24)

To a solution of dry cis-4-(1-aminocyclopropyl)-4-phenylcyclohexanol (4,0.2 g, 0.75 mmol) in anhydrous N,N-dimethylacetamide (5 mL) at 0° C. wasadded portionwise sodium hydride (60% in mineral oil, 0.12 g, 3 mmol).The reaction mixture was stirred for 10 min at room temperature,1-(benzyloxy)-7-chloro-6-fluoroisoquinoline (38, 0.28 g, 0.97 mmol) wasthen added and stirring was continued overnight. The suspension waspoured onto ice, the resulting precipitate was filtered and dried. Thecrude product was purified by chromatography on silica gel (eluting with0 to 5% methanol in dichloromethane containing 1% ammonia) to yield0.252 g of the desired product. R_(t)=6.21 min (Method 9). Detectedmass: 499 (M+H⁺).

b)cis-6-[4-(1-Amino-cyclopropyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one(Example 2)

To a solution ofcis-1-[4-[[7-chloro-1-(phenylmethoxy)-6-isoquinolinyl]oxy]-1-phenylcyclohexyl]-cyclopropanamine(24, 0.24 g, 0.48 mmol) in isopropanol (2.5 mL) was added a solution of4N aqueous hydrochloric acid (2.5 mL, 10 mmol) followed by 2.5 mL ofisopropanol, 2.5 mL of 4N aqueous hydrochloric acid (10 mmol) andeventually 2.5 mL of methanol. The resulting suspension was stirredovernight, evaporated under reduced pressure and co-evaporated with amethanol/toluene mixture. The crude product was triturated withmethanol/diethyl ether to afford 0.18 g of the title compound as itshydrochloride. R_(t)=4.83 min (Method 9). Detected mass: 409 (M+H⁺).

Example 3cis-6-{[4-(1-aminopropyl)-4-phenylcyclohexyl]oxy}-7-chloro-2H-isoquinolin-1-onea)cis-1-(4-{[1-(benzyloxy)-7-chloroisoquinolin-6-yl]oxy}phenylcyclohexyl)-propanamine(25)

To a solution of cis-4-(1-aminopropyl)-4-phenylcyclohexanol (6, 0.39 g,1.48 mmol) in anhydrous N,N-dimethylacetamide (10 mL) was addedportionwise sodium hydride (60% in mineral oil, 0.24 g, 5.92 mmol). Thereaction mixture was stirred for 10 min at room temperature, then1-(benzyloxy)-7-chloro-6-fluoroisoquinoline (38, 0.42 g, 1.48 mmol) wasadded and stirring was continued for 72 hours. The suspension was pouredonto ice, the resulting aqueous layer was extracted with chloroform. Theorganic layers were dried over sodium sulphate, filtered andconcentrated under reduced pressure. The crude product was purified bychromatography on silica gel (eluting with 0 to 10% methanol indichloromethane) to yield 0.604 g ofcis-1-(4-{[1-(benzyloxy)-7-chloroisoquinolin-6-yl]oxy}-1-phenylcyclohexyl)propanamine(25). R_(t)=4.18 min (Method 8). Detected mass: 501 (M+H⁺).

b)cis-6-{[4-(1-aminopropyl)-4-phenylcyclohexyl]oxy}-7-chloro-2H-isoquinolin-1-one(Example 3)

To a solution ofcis-1-(4-{[1-(benzyloxy)-7-chloroisoquinolin-6-yl]oxy}-1-phenylcyclohexyl)propanamine(25, 0.604 g, 1.21 mmol) in isopropanol (6.3 mL) was added a solution of1N aqueous hydrochloric acid (7 mL, 7 mmol). The resulting suspensionwas stirred overnight and evaporated under reduced pressure. The crudeproduct was purified by reversed phase column chromatography (elutingwith 0 to 30% CH₃CN in water) to afford the title compound (0.32 g).R_(t)=5.00 min (Method 9). Detected mass: 411 (M+H⁺).

The following examples were prepared in a similar fashion as describedfor Example 1, starting from a suitably protected isoquinolinone and therespective aminoalcohol.

Aminoalcohols were synthesized from the corresponding benzonitriles andgrignard reagents: trans-aminoalcohols were obtained in a similarfashion as described in the reaction sequence to yield (19),cis-aminoalcohols were obtained in a similar fashion as described in thereaction sequence to yield (14). Dimethylated aminoalcohols wereobtained in a similar fashion as described for (22). All describedproducts were obtained as the hydrochloride salts.

Ex. Isoqui- R_(t)/ No. noline Product Chemical Name [M + H⁺] [min]Method 4 10

cis-6-[4-(1- Amino-butyl)-4- phenyl-cyclo hexyloxy]-7- chloro-2H-isoquinolin-1- one 425.2 2.61 1 5 10

cis-6-[4-(1- Amino-butyl)-4- (4-fluoro- phenyl)-cyclo- hexyloxy]-7-chloro-2H- isoquinolin-1- one 443.2 2.66 1 6 10

cis-6-[4-(1-Amin- propyl)-4-(4- bromo-phenyl)- cyclo hexyloxy]-7-chloro-2H- isoquinolin-1- one 489.1 2.69 1 7 10

cis-6-[4-(1- Amino-propyl)-4- (2-bromo- phenyl)-cyclo hexyloxy]-7-chloro-2H- isoquinolin-1- one 489.1 2.64 1 8 10

cis-6-[4-(1- Amino-propyl)-4- (4-trifluoro methyl-phenyl)-cyclo-hexyloxy]- 7-chloro-2H- isoquinolin-1- one 479.2 2.74 1 9 10

cis-6-[4-(1- Amino-propyl)-4- (2-fluoro- phenyl)-cyclo hexyloxy]-7-chloro-2H- isoquinolin-1- one 429.2 2.52 1 10 10

cis-6-[4-(1- Amino-propyl)-4- (2-chloro- phenyl)- cyclohexyloxy]-7-chloro-2H-iso quinolin-1-one 445.1 2.71 1 11 39

cis-6-[4-(1- Amino-propyl)-4- phenyl- cyclohexyloxy]-7- methyl-2H-isoquinolin-1-one 391.2 2.56 1 12 38

trans-6-[4-(1- Amino-butyl)-4- (4-fluoro- phenyl)- cyclohexyloxy]-7-chloro-2H- isoquinolin-1- one 443.2 2.63 1 13 38

trans-6-[4-(1- Amino-ethyl)-4- (4-fluoro- phenyl)- cyclohexyloxy]-7-chloro-2H- isoquinolin-1- one 415.2 2.48 1 14 38

trans-6-[4-(1- Amino-butyl)-4- phenyl- cyclohexyloxy]- 7-chloro-2H-isoquinolin-1- one 425.2 2.67 1 15 38

cis-6-[4-(1- Amino-ethyl)-4- (4-fluoro- phenyl)-cyclo- hexyloxy]-7-chloro-2H-iso quinolin-1-one 415.2 2.48 1 16 10

trans-6-[4-(1- Amino-propyl)-4- (3-bromo- phenyl)-cyclo hexyloxy]-7-chloro-2H-iso quinolin-1-one 489.2 2.77 2 17 10

trans-6-[4-(1- Amino-propyl)-4- (3-methoxy- phenyl)-cyclo hexyloxy]-7-chloro-2H-iso quinolin-1-one 441.2 2.65 2 18 10

trans-6-[4- (Amino-phenyl- methyl)-4-(4- fluoro-phenyl)- cyclohexyloxy]-7-chloro-2H- isoquinolin-1- one 477.2 2.67 1 19 10

trans-6-[4-(1- Amino-2-methyl- propyl)-4- phenyl-cyclo hexyloxy]-7-chloro-2H-iso quinolin-1-one 425.3 3.33 6 20 10

trans-6-[4-(1- Amino-3-methyl- butyl)-4-phenyl- cyclohexyloxy]-7-chloro-2H-iso quinolin-1-one 439.4 2.74 1 21 10

trans-6-[4- (Amino-phenyl- methyl)-4- phenyl-cyclo- hexyloxy]-7-chloro-2H-iso quinolin-1-one 458.2 2.78 1 22 38

trans-6-[4-(1- Amino-1-methyl- ethyl)-4-(4- fluoro-phenyl)-cyclohexyloxy]- 7-chloro-2H-iso quinolin-1-one 429.1 2.64 1 23 38

cis-6-[4-(1- Amino- cyclopropyl)-4- (2-fluoro- phenyl)-cyclohexyloxy]-7- chloro-2H-iso quinolin-1-one 427 3.29 8 24 38

cis-6-[4-(1- Amino-ethyl)-4- phenyl-cyclo hexyloxy]-7- chloro-2H-isoquinolin-1-one 397 3.19 8 25 38

cis-6-[4-(1- Amino-1-methyl- ethyl)-4-phenyl- cyclo-hexyloxy]-7-chloro-2H-iso quinolin-1-one 411 0.62 7 26 38

cis-6-(4-[amino (cyclopropyl) methyl]-4- phenyl-cyclo- hexyl}oxy)-7-chloro-2H-iso quinolin-1-one 423 5.10 9 27 10

cis-6-[4-(1- Amino-propyl)-4- (4-isopropyl- phenyl)-cyclo hexyloxy]-7-chloro-2H-iso quinolin-1-one 453.2 1.20 5 28 10

cis-6-[4-(1- Amino-propyl)-4- (3-methoxy)- phenyl)-cyclo hexyloxy]-7-chloro-2H-iso quinolin-1-one 441.2 1.07 5 29 10

cis-6-[4-(1- Amino-propyl)-4- (3-bromo- phenyl)-cyclo hexyloxy]-7-chloro-2H-iso quinolin-1-one 503.1 1.34 5 30 10

cis-6-[4-(1- Amino-2-methyl- propyl)-4-(4- fluoro-phenyl)-cyclohexyloxy]- 7-chloro-2H- isoquinolin-1- one 443.2 2.66 1 31 10

trans-6-[4-(1- amino-propyl)-4- (4-fluoro- phenyl)-cyclo hexyloxy]-7-chloro-2H-iso quinolin-1-one 429.2 2.57 1 32 38

trans-6-[4-(1- amino-propyl)-4- phenyl)- cyclohexyloxy]- 7-chloro-2H-isoquinolin-1- one 411.2 2.69 1 55 10

cis-6-[4-(1- Amino-propyl)-4- pyridin-2-yl- cyclohexyloxy]- 7-chloro-2H-isoquinolin-1- one 412.2 1.77 13 56 10

cis-6-[4-(1- Amino-propyl)-4- (2,4-difluoro- phenyl)- cyclohexyloxy]-7-chloro-2H- isoquinolin-1- one 447.1 1.84 12 57 10

cis-6-[4-(1- Amino-propyl)-4- (4-fluoro-2- methyl-phenyl)cyclohexyloxy]- 7-chloro-2H- isoquinolin-1- one 443.1 1.89 12 58 10

cis-6-[4-(1- Amino-propyl)-4- (3,5-difluoro- phenyl)- cyclohexyloxy]-7-chloro-2H- isoquinolin-1- one 447.1 1.86 12 59 10

cis-6-[4-(1- Amino-propyl)-4- (3,4-difluoro- phenyl)-cyclo hexyloxy]-7-chloro-2H- isoquinolin-1- one 447.1 1.87 12 60 10

cis-6-[4-(1- Amino-propyl)-4- o-tolyl- cyclohexyloxy]- 7-chloro-2H-isoquinolin-1- one 425.1 1.82 12 61 10

cis-6-[4-(1- Amino-propyl)-4- (2-trifluoro methoxy- phenyl)-cyclohexyloxy]- 7-chloro-2H-iso quinolin-1-one 495.2 1.97 12 62 10

cis-6-[4-(1- Amino-propyl)-4- (4-fluoro-3- methoxy- phenyl)-cyclohexyloxy]- 7-chloro-2H-iso quinolin-1-one 459.3 1.28 16 63 10

cis-6-[4-(1- Amino-propyl)-4- (3-ethoxy- phenyl)- cyclohexyloxy]-7-chloro-2H- isoquinolin-1- one 455.3 1.24 16 64 10

cis-6-[4-(1- Amino-propyl)-4- (3-methoxy-4- methyl-phenyl)-cyclohexyloxy]- 7-chloro-2H- isoquinolin-1- one 438.2 (M + H⁺ − NH₃)3.69 3 65 52

cis-6-[4-(1- Amino-propyl)-4- (3,4-difluoro- phenyl)-cyclo hexyloxy]-7-methyl-2H- isoquinolin-1- one 427.2 1.38 10 66 50

cis-6-[4-(1- Amino-propyl)-4- (3,5-difluoro- phenyl)- cyclohexyloxyl-7-fluoro-2H- isoquinolin-1- one 431.2 1.36 10 67 51

cis-6-[4-(1- Amino-propyl)-4- (3,4-difluoro- phenyl)-cyclo hexyloxy]-7-fluoro-5-methyl- 2H-isoquinolin- 1-one 445.3 0.98 11 68 54

cis-6-[4-(1- Amino-propyl)-4- (3,5-difluoro- phenyl)-cyclo hexyloxy]-7-methoxy-2H- isoquinolin-1- one 443.3 0.96 11 69 10

cis-6-[4-(1- Amino-propyl)-4- (2-methoxy- phenyl)- cyclohexyloxy]-7-chloro-2H isoquinolin-1- one 441.2 1.88 13 70 10

cis-6-[4-(1- Amino-propyl)-4- (4-trifluoro- methoxy- phenyl)-cyclohexyloxy]- 7-chloro-2H- isoquinolin-1- one 495.2 2.32 14 717-Chloro- 6-fluoro- isoquinoline

cis-1-[4-(7- Chloro- isoquinolin-6- yloxy)-1-(3,4- difluoro-phenyl)-cyclohexyl]- propylamine 431.3 2.28 2 72 46

cis-1-[4-(7- Bromo-iso quinolin-6- yloxy)-1-(3,4- difluoro-phenyl)-cyclohexyl]- propylamine 475.3 2.34 2 73 44

cis-1-[1-(3,5- Difluoro-phenyl)- 4-(5,7-dimethyl- isoquinolin-6- yloxy)-cyclohexyl]- propylamine 425.3 0.87 11 74 43

cis-1-[1-(3,5- Difluoro-phenyl)- 4-(7-fluoro-5- methyl- isoquinolin-6-yloxy)- cyclohexyl]- propylamine 429.3 1.30 10 75 45

cis-1-[1-(3,4- Difluoro-phenyl)- 4-(7-fluoro- isoquinolin-6- yloxy)-cyclohexyl]- propylamine 415.3 2.24 2 76 7-Chloro-6- fluoro-isoquinoline

cis-1-[4-(7- Chloro- isoquinolin-6- yloxy)-1-(3,5- difluoro-phenyl)-cyclohexyl]- propylamine 431.1 1.20 10 77 10

cis-6-[4-(1- Amino-1-methyl- ethyl)-4-(4- fluoro-phenyl)-cyclohexyloxy]- 7-chloro-2H- isoquinolin-1- one 431.3 0.70 15 78 55

cis-6-[4-(1- Amino-propyl)-4- (3,5-difluoro- phenyl)- cyclohexyloxy]-4-benzyl-7- chloro-2H- isoquinolin-1- one 537.2 1.50 10 79 49

cis-6-[4-(1- Amino-propyl)-4- (3,5-difluoro- phenyl)- cyclohexyloxy]-5-chloro-2H- isoquinolin-1- one 447.2 1.33 10 80 53

cis-6-[4-(1- Amino-propyl)-4- (3,5-difluoro- phenyl)- cyclohexyloxy]-5,7-dimethyl-2H- isoquinolin-1- one 441.3 3.24 6 81 5-Chloro-6- fluoro-isoquinoline

cis-1-[4-(5- Chloro- isoquinolin-6- yloxy)-1-(3,5- difluoro-phenyl)-cyclohexyl]- propylamine 431.1 1.21 10 82 10

cis-6-[4-(Amino- cyclopropyl- methyl)-4-(4- fluoro-phenyl)-cyclohexyloxy]- 7-chloro-2H- isoquinolin-1- one 441.2 1.86 13 83 10

cis-6-[4-(1- Amino-propyl)-4- (3- trifluoromethyl- phenyl)-cyclohexyloxy]- 7-chloro-2H- isoquinolin-1- one 479.1 3.26 3 84 10

cis-6-[4-(1- Amino-propyl)-4- (3-trifluoro methoxy- phenyl)-cyclohexyloxy]-7- chloro-2H-iso quinolin-1-one 495.1 1.97 12 85 52

cis-6-[4-(1- Amino-propyl)-4- (3-trifluoro- methoxy- phenyl)-cyclo-hexyloxy]-7- methyl-2H-iso quinolin-1-one 475.3 1.36 16 86 52

cis-6-[4-(1- Amino-propyl)-4- (3-trifluoro methyl-phenyl)-cyclohexyloxy]- 7-methyl-2H-iso quinolin-1-one 459.2 1.32 16 87 50

cis-6-[4-(1- Amino-propyl)-4- phenyl-cyclo hexyloxy]-7- fluoro-2H-isoquinolin-1-one 395.2 1.37 10 88 51

cis-6-[4-(1- Amino-propyl)-4- phenyl-cyclo hexyloxy]-7- fluoro-5-methyl-2H-isoquinolin- 1-one 409.3 0.96 11 89 7-chloro-6- fluoro- isoquinoline

cis-1-[4-(7- Chloro-iso- quinolin-6- yloxy)-1-phenyl- cyclohexyl]-propylamine 395.2 1.20 10 90 44

cis-1-[4-(5,7- Dimethyl- isoquinolin-6- yloxy)-1-phenyl- cyclohexyl]-propylamine 389.3 0.86 11 91 45

cis-1-[4-(7- Fluoro- isoquinolin-6- yloxy)-1-phenyl- cyclohexyl]-propylamine 379.2 1.16 10 92 5-chloro-6- fluoro- isoquinoline

cis-1-[4-(5- Chloro- isoquinolin-6- yloxy)-1-phenyl- cyclohexyl]-propylamine 395.2 1.18 10 93 43

cis-1-[4-(7- Fluoro-5-methyl- isoquinolin-6- yloxy)-1-phenyl-cyclohexyl] propylamine 393.2 1.20 10 94 46

cis-1-[4-(7- Bromo- isoquinolin-6- yloxy)-1-phenyl- cyclohexyl]-propylamine 439.1 1.19 10 95 48

cis-1-[4-(7- Methyl- isoquinolin-6- yloxy)-1-phenyl- cyclohexyl]-propylamine 375.3 1.22 10 96 55

cis-6-[4-(1- Amino-propyl)-4- phenyl-cyclo hexyloxy]-4- benzyl-7-chloro-2H-isoquinolin- 1-one 501.3 1.50 10

Example 33cis-6-[4-(1-Amino-propyl)-4-phenyl-cyclohexyloxy]-4-bromo-7-chloro-2H-isoquinolin-1-one

100 mg of Example 3 were dissolved in 3 mL of chloroform. 100 μL oftriethylamine and 268 μL of a 1M solution of bromine in chloroform wereadded. The reaction was stirred at room temperature until conversion wascomplete. The mixture was quenched by addition of 11 mL sat. sodiumthiosulfate solution. 5 mL of 2N sodium hydroxide solution were addedand the aqueous layer was extracted three times withdichloromethane:isopropanol (3:1). The combined organic layer was washedwith 2N NaOH and brine, dried over sodium sulphate and evaporated. Themixture was purified by HPLC and the obtained product was dissolved in 1mL of isopropanol:1N HCl and heated in a microwave oven for 20 minutesat 100° C. The mixture was evaporated to dryness, taken up in water andlyophilized to give 29 mg of the desired product as the hydrochloride.R_(t)=2.77 min (Method 1). Detected mass: 491.1 (M+H⁺).

cis-{1-[1-(4-Bromo-phenyl)-4-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-cyclohexyl]-propyl}-carbamicacid tert-butyl ester (81)

1.11 g of Example 6 were dissolved in 100 mL of dry dichloromethane. 1.2mL of triethylamine and 1.44 g of di-tert.butyl dicarbonate were added.After conversion was complete, the mixture was extracted with 1N sodiumhydroxide solution, 0.2 N hydrochloric acid, water and brine, dried andevaporated. The crude product was purified by silica gel filtration togive 886 mg of the desired product. R_(t)=4.00 min (Method 1). Detectedmass: 533.0 (M+H-isobutene⁺).

Example 97cis-4-[1-(1-Amino-propyl)-4-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-cyclohexyl]benzonitrile

200 mg of 81 were dissolved in 10 mL of degassed dimethyl formamide and50 mg of zinc cyanide and 18 mg oftetrakis(triphenylphosphine)palladium(0) were added under argon. Themixture was heated in a microwave oven for 30 minutes at 150° C. Themixture was diluted with methyl tert. butyl ether and filtered overCelite. The organic layer was washed twice with water and once withbrine, dried over sodium sulphate and evaporated to dryness. The crudeproduct was purified by silica gel chromatography and subsequently takenup in 2 mL of isopropanol and 2 mL of 1N hydrochloric acid and heated ina microwave oven at 100° C. for 1 hour. Water was added and the mixturewas lyophilized. The residue was taken up in water and lyophilized againto give 65 mg of the desired product as hydrochloride. R_(t)=2.55 min(Method 2). Detected mass: 436.2 (M+H⁺).

Example 98cis-3-[1-(1-Amino-propyl)-4-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-cyclohexyl]benzonitrile

Example 98 can be obtained following a similar reaction sequence as usedfor the synthesis of Example 97, starting from Example 16. R_(t)=2.98min (Method 3). Detected mass: 436.2 (M+H⁺).

Example 996-[cis-4-(1-Amino-propyl)-4-(3-methanesulfonyl-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-onea)cis-{1-[4-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-1-(3-methanesulfonyl-phenyl)-cyclohexyl]-propyl-carbamicacid tert-butyl ester (82)

330 mg (559 μmol) ofcis-{1-[1-(3-Bromo-phenyl)-4-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-cyclohexyl]-propyl}-carbamicacid tert-butyl ester (obtained from Example 29 as described forsynthesis of 81), 213 mg (1.1 mmol) CuI and 114 mg (1.1 mmol)methansulfinic acid sodium salt were dissolved in 10 mL of anhydrousNMP. The mixture was stirred at 150° C. for 1 h under microwaveirradiation, then poured into 100 mL of a saturated aqueousNaHCO₃-solution and extracted three times using 30 mL of ethyl acetateeach. The organic layer was then washed five times using 20 mL of watereach, dried over MgSO₄, filtered and the solvent removed under reducedpressure. Flash chromatography using ethyl acetate yielded 143 mg of 82as a viscous oil. R_(f) (ethyl acetate): 0.33

b) Example 99cis-6-[4-(1-Amino-propyl)-4-(3-methanesulfonyl-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one

140 mg (238 μmol) ofcis-{1-[4-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-1-(3-methanesulfonyl-phenyl)-cyclohexyl]propyl-carbamicacid tert-butyl ester (82) were dissolved in 3 mL of isopropanol and 3mL of a 2N aqueous solution of HCl added. The mixture was stirred for 20h at ambient temperature, diluted with 30 mL of water and freeze driedto yield 120 mg of Example 99 as its hydrochloride as an amorphoussolid. R_(t)=0.66 min (Method 18). Detected mass: 489.2 (M+H⁺)

Example 1006-[(1S,4S,5S)-5-(1-Amino-propyl)-5-phenyl-bicyclo[2.2.1]hept-2-yloxy]-7-chloro-2H-isoquinolin-1-onea) 5-Oxo-bicyclo[2.2.1]heptane-2-carbonitrile ethylene ketal (83)

9.0 g (71 mmol) of 2-cyclopen-1-one ethylene ketal, 11.4 g (214 mmol) ofacrylonitrile and 150 mg (1.4 mmol) of hydroquinone were mixed andheated to 150° C. for 1 h under microwave irradiation. The excess ofacrylonitrile was removed under reduced pressure and the residuedissolved using 150 mL of diethylether. This solution was washed threetimes using 50 mL of saturated aqueous Na₂CO₃-solution each, dried overMgSO₄ and evaporated. The resulting oil was dissolved in 200 mL ofcyclohexane and 100 mL of diethylether, washed three times using 50 mLof an aqueous 0.1 N NaOH-solution and twice using 100 mL of a saturatedaqueous NaCl-solution. The organic layer was dried over MgSO₄, filteredand the solvent evaporated to yield 7.3 g of 83 as a colourless oil.

b) (1S,2S,4S)-5-Oxo-2-phenyl-bicyclo[2.2.1]heptane-2-carbonitrileethylene ketal and(1R,2R,4R)-5-Oxo-2-phenyl-bicyclo[2.2.1]heptane-2-carbonitrile ethyleneketal (84 and 85)

7.5 g (42 mmol) of 5-Oxo-bicyclo[2.2.1]heptane-2-carbonitrile ethyleneketal (83) and 4.4 g (46 mmol) of fluorobenzene were dissolved in 10 mLof anhydrous toluene. The mixture was stirred at 65° C. for 20 h, thenpoured into 300 mL of a saturated aqueous NaHCO₃-solution, and extractedtwice using 100 mL ethyl acetate each. The organic layer was dried usingMgSO₄ and evaporated. Chromatography on reversed phase(acetonitrile/water) yielded 3.4 g of the racemic mixture as a singlediastereomer as colourless oil.

Chromatography on chiral phase (Chiralpak AD-H, 250×4.6 mm) usingn-heptane:2-propanol:methanol 5:1:1 yielded 1.4 g of 84 (R_(t)=7.4 min)and 1.4 g of 85 (R_(t)=9.3 min). R_(t)=1.44 min (Method 5). Detectedmass: 256.3 (M+H⁺)

The absolute stereochemistry was assigned arbitrarily.

c) (1S,2S,4S)-5-Oxo-2-phenyl-bicyclo[2.2.1]heptane-2-carbonitrile (86)

1.3 g of (1S,2S,4S)-5-Oxo-2-phenyl-bicyclo[2.2.1]heptane-2-carbonitrileethylene ketal (84) were dissolved in a mixture of 30 mL THF and 30 mLof a 5% aqueous HCl-solution and kept at ambient temperature for 30 h.The mixture was diluted using 100 mL of a saturated aqueousNaCl-solution and 100 mL of ethyl acetate. After separation, the aqueouslayer was extracted twice using 50 mL of ethyl acetate each. The organiclayer was dried using MgSO₄ and evaporated to give 1.2 g of (86) as acolourless oil.

[α]_(D)=+5.6° (c=0.013 in methanol), R_(t)=1.27 min (Method 5).

d) (1S,2S,4S)-5-Hydroxy-2-phenyl-bicyclo[2.2.1]heptane-2-carbonitrile(87)

0.9 g (4.3 mmol) of(1S,2S,4S)-5-Oxo-2-phenyl-bicyclo[2.2.1]heptane-2-carbonitrile (86) weredissolved using 20 mL of ethanol and 161 mg (4.3 mmol) of NaBH₄ wasadded at −70° C. The mixture was stirred at ambient temperature for 1 h,100 mL of a saturated aqueous NaCl-solution was added and the pHadjusted to 2-3 using aqueous HCl-solution. The mixture was extractedthree times using 50 mL of ethyl acetate each. The organic layer wasdried over MgSO₄ and evaporated to yield 0.9 g of (87) as a singlediastereomer as a colourless oil. R_(t)=0.76 min (Method 18). Detectedmass: 214.1 (M+H⁺)

e)(1S,2S,4S)-5-(tert-Butyl-dimethyl-silanyloxy)-2-phenyl-bicyclo[2.2.1]heptane-2-carbonitrile(88)

0.9 g (4.2 mmol) of(1S,2S,4S)-5-Hydroxy-2-phenyl-bicyclo[2.2.1]heptane-2-carbonitrile (87)and 1.1 g (10.6 mmol) of 2,6-lutidine were dissolved in 40 mL ofdichloromethane. 1.3 g (5.1 mmol) of tert-butyldimethylsilyltrifluormethanesulfonate were added at −10° C. The mixture was stirredat ambient temperature for 17 h.

Afterwards, additional 500 mg of 2,6-lutidine and 600 mg oftert-butyldimethylsilyl trifluormethanesulfonate were added at −10° C.and the mixture stirred at ambient temperature for 48 h. Afterwards,additional 1.1 g of 2,6-lutidine and 1.3 g of tert-butyldimethylsilyltrifluormethanesulfonate were added at −10° C. and the mixture stirredat ambient temperature for 24 h. The mixture was evaporated, the residuedissolved using 100 mL of ethyl acetate and washed using three times 50mL of a saturated aqueous Na₂CO₃-solution each, three times 50 mL of a0.5 N aqueous HCl-solution each and finally once using 50 mL of asaturated aqueous Na₂CO₃-solution. The organic layer was dried using amixture of MgSO₄ and K₂CO₃, filtered and evaporated. Flashchromatography on silica gel using ethyl acetate/n-heptane 1:2 yielded970 mg of (88) as a colourless oil. R_(f) (ethyl acetate/n-heptane1:2)=0.8. R_(t)=1.32 min (Method 18).

f) (1S,4S,5S)-5-(1-Amino-propyl)-5-phenyl-bicyclo[2.2.1]heptan-2-ol (89)

930 mg (2.8 mmol) of(1S,2S,4S)-5-(tert-Butyl-dimethyl-silanyloxy)-2-phenyl-bicyclo[2.2.1]heptane-2-carbonitrile(88) were dissolved in 10 mL of anhydrous toluene. Afterwards, 5.7 mL ofa 1M solution of ethylmagnesium bromide in THF was added and the mixturewas heated under reflux for 12 h. The mixture was then treated with 3 mLethanol and evaporated. The residue was dissolved in 20 mL of ethanoland 215 mg (5.7 mmol) of NaBH₄ was added. The mixture was stirred atambient temperature for 3 h and then evaporated. The residue wasdissolved using 100 mL of water, the pH adjusted to 3 using aqueousHCl-solution to remove excess NaBH₄ and then adjusted to pH=12 usingsaturated aqueous Na₂CO₃-solution. The mixture was extracted three timesusing 30 mL of t-butylmethylether each. Afterwards, the organic layerwas extracted twice using 20 mL of a 1N aqueous HCl-solution each, theaqueous layer was adjusted to pH>11 using saturated aqueousNa₂CO₃-solution and extracted three times using 30 mL t-butylmethylethereach. The organic layer was dried using MgSO₄ and evaporated yielding200 mg of the desired product 89, used without further purification.R_(t)=0.58 min (Method 18).

g)1-[(1S,2S,4S)-5-(7-Chloro-1-methoxy-isoquinolin-6-yloxy)-2-phenyl-bicyclo[2.2.1]hept-2-yl]-propylamine(90)

200 mg (0.82 mmol) of(1S,4S,5S)-5-(1-Amino-propyl)-5-phenyl-bicyclo[2.2.1]heptan-2-ol (89)were dissolved in 5 mL anhydrous dimethylacetamide. Afterwards, 39 mg(1.63 mmol) of NaH were added, followed by the addition of 173 mg (0.82mmol) of 7-chloro-6-fluoro-1-methoxy-isoquinoline (10). The mixture wasstirred at ambient temperature for 20 h. Afterwards, 50 mL of asaturated aqueous NaHCO₃-solution were added and the mixture extractedthree times using 30 mL ethyl acetate each. The organic layer was driedusing MgSO₄ and evaporated. The residue was purified usingchromatography on reversed phase (acetonitrile/water). Theproduct-containing fractions were evaporated to half of the originalvolume, 10 mL of a saturated aqueous Na₂CO₃-solution was added and themixture extracted three times using 20 mL of ethyl acetate each. Theorganic layer was dried using MgSO₄, filtered and evaporated yielding 34mg of the desired product 90. R_(t)=0.86 min (Method 18). Detected mass:437.3 (M+H⁺)

h)6-[(1S,4S,5S)-5-(1-Amino-propyl)-5-phenyl-bicyclo[2.2.1]hept-2-yloxy]-7-chloro-2H-isoquinolin-1-one(Example 100)

35 mg of1-[(1S,2S,4S)-5-(7-Chloro-1-methoxy-isoquinolin-6-yloxy)-2-phenyl-bicyclo[2.2.1]hept-2-yl]-propylamine(90) were dissolved using 1 mL of 2-propanol and 1 mL of a 1N aqueousHCl-solution. The mixture was heated to 100° C. for 1 h under microwaveirradiation. Afterwards, 20 mL of water were added and the mixturefreeze dried. The residue was once again treated with 20 mL of water andfreeze dried to yield 34 mg of the desired product as its hydrochloride.R_(t)=0.75 min (Method 18). Detected mass: 423.2 (M+H⁺)

Example 1016-[(1R,4R,5R)-5-(1-Amino-propyl)-5-phenyl-bicyclo[2.2.1]hept-2-yloxy]-7-chloro-2H-isoquinolin-1-one

Example 101 has been synthesized as its hydrochloride in analogy to thesynthesis of example 100 starting from7-chloro-6-fluoro-1-methoxy-isoquinoline (10) and(1R,2R,4R)-5-oxo-2-phenyl-bicyclo[2.2.1]heptane-2-carbonitrile ethyleneketal (85). R_(t)=0.75 min (Method 18). Detected mass: 423.2 (M+H⁺)

Example 102cis-6-[4-(1-Benzylamino-propyl)-4-phenyl-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one

60 mg of Example 11 were dissolved in 850 μL of methanol, then 39 μL oftriethylamine, 80 μL of acetic acid, 50 mg of powdered molecular sievesand 43 μL of benzaldehyde were added and the mixture was allowed to stirfor 1 h. A solution of 26 mg of sodium cyanoborohydride in 200 μL ofmethanol was added and the mixture was stirred at 40° C. for 5 min. Thereaction mixture was filtered and the filtrate was evaporated todryness. The residue was dissolved in 50 mL of dichloromethane andwashed with saturated sodium bicarbonate solution. The aqueous phase wasreextracted twice with dichloromethane. The combined organic layer wasdried over magnesium sulphate, filtered, evaporated and the crudematerial was purified by reversed phase HPLC (acetonitrile/water) toyield 27 mg of the desired product as trifluoroacetic acid salt.R_(t)=2.94 min (Method 2). Detected mass: 481.4 (M+H⁺).

The following examples were obtained in a similar fashion as describedfor example 102, using the respective isoquinolines and aldehydes asstarting materials:

Ex. Start. Alde- Chemical [M + R_(t)/ Meth- No. Product Mat. hyde NameH⁺] [min] od 103

Ex. 11 Acet- alde- hyde cis-6-[4-(1- Diethylamino- propyl)-4-phenyl-cyclo hexyloxy]-7- methyl-2H- isoquinolin-1- one 447.4 2.73  2104

Ex. 86 Pro- panal cis-7-Methyl-6- [4-(1-propyl amino-propyl)-4-(3-trifluoro methyl- phenyl)-cyclo hexyloxy]-2H- isoquinolin-1- one501.2 1.50 10 105

Ex. 3 Benz- alde- hyde cis-6-[4-(1- Benzylamino- propyl)-4- phenyl-cyclohexyloxy]- 7-chloro-2H- isoquinolin-1- one 501.3 1.47 10 106

Ex. 3 Iso- butyr- alde- hyde cis-7-Chloro-6- [4-(1-isobutylamino-propyl)- 4-phenyl- cyclohexyloxy]- 2H-iso quinolin-1-one 467.31.45 10 107

Ex. 3 Buta- nal cis-6-[4-(1- Butylamino- propyl)-4- phenyl-cyclohexyloxy]-7- chloro-2H- isoquinolin-1- one 501.3 1.46 10 108

Ex. 3 Cyclo propyl carbox aldehyde cis-7-Chloro-6- {4-[1-(cyclopropylmethyl- amino)-propyl]- 4-phenyl- cyclohexyl oxy}-2H-isoquinolin-1- one 465.3 1.43 10

cis-4-(tert-Butyl-dimethyl-silanyloxy)-1-(4-fluoro-phenyl)-cyclohexanecarb-aldehyde(91)

To a solution of 9.74 g (29.2 mmol) ofcis-4-(tert-butyl-dimethyl-silanyloxy)-1-(4-fluoro-phenyl)-cyclohexane-carbonitrile(78) in 290 mL of dichloromethane at −70° C. were added over a period of20 min 73 mL (73 mmol) of a solution of diisobutylaluminium hydride indichloromethane (1M). The reaction mixture was stirred for 1 h at −70°C., before 250 mL of 10% aqueous potassium sodium tartrate solution wereadded and the resulting biphasic system was vigourously stirred for 2 hat room temperature. 200 mL of ethyl acetate were added and the phaseswere separated. The aqueous phase was extracted with 150 mL of ethylacetate and the combined organic phases were dried over magnesiumsulphate, filtered and concentrated. The resulting oil was purified bysilica gel chromatography (heptanes:ethyl acetate) to give 8.38 g of thedesired product. R_(t)=1.09 min (Method 17). Detected mass: 337.2(M+H⁺).

cis-[4-(tert-Butyl-dimethyl-silanyloxy)-1-(4-fluoro-phenyl)-cyclohexyl]-acetonitrile(92)

To an ice-cold solution of 6.60 g (19.6 mmol) ofcis-4-(tert-butyl-dimethyl-silanyloxy)-1-(4-fluoro-phenyl)cyclohexanecarbaldehyde(91) in 50 mL of dry methanol were added portionwise 1.48 g (39.2 mmol)of sodium borohydride. The reaction mixture was stirred for 1 h at 0°C., then 16 h at room temperature, before being quenched by addition of70 mL of water. The solution was extracted three times with ethylacetate (100 mL each). The organic phases were combined, washed withbrine, dried over magnesium sulphate, filtered and evaporated todryness.

The resulting alcohol (6.17 g crude) was dissolved in 50 mL of drydichloromethane and cooled to 0° C. 2.56 mL (1.84 g, 18.2 mmol) oftriethylamine were added and the mixture stirred for 5 min. Then, 3.53mL (5.22 g, 45.6 mmol) of methanesulfonylchloride was added dropwise andthe solution was stirred for 2.5 h at 0° C. The reaction mixture wastreated with 50 mL of water and stirred for 30 min at room temperature.The phases were separated and the aqueous phase was extracted twice with100 mL dichloromethane. The organic phases were combined, washed withbrine, dried over magnesium sulphate, filtered and evaporated todryness. The crude product was purified by silica gel chromatography(heptanes:ethyl acetate) to give 5.20 g of the desired mesylate, whichwas dissolved in 200 mL of dry dimethylformamide and treated with 4.06 g(62.4 mmol) of potassium cyanide and 6.60 g (25.0 mmol) of 18-crown-6.The orange solution was heated to 155° C. for 36 h and stirred 16 h atroom temperature before being poured onto 200 mL of a mixture of waterand ice. The mixture was extracted twice with ethyl acetate. The organicphases were combined, dried over magnesium sulphate, filtered andconcentrated. The crude product was purified by silica gelchromatography (heptanes:ethyl acetate) to give 1.22 g of the desiredproduct 92. R_(t)=1.04 min (Method 17). Detected mass: 348.2 (M+H⁺).

cis-4-(2-Amino-propyl)-4-(4-fluoro-phenyl)-cyclohexanol (93)

Under argon, 260 mg (0.75 mmol) ofcis-[4-(tert-butyl-dimethyl-silanyloxy)-1-(4-fluoro-phenyl)-cyclohexyl]-acetonitrile(92) were dissolved in 5 mL of absolute toluene. Then, 500 μL ofmethylmagnesium bromide (3M in diethylether) were added dropwise and thereaction mixture was heated to 80° C. for 2 h. After cooling to roomtemperature, 3 mL of dry methanol were added. After a period of 10 min,28.3 mg (1.45 mmol) of sodium borohydride were added and the mixture wasstirred for 3 h at room temperature. The reaction was quenched byaddition of 1M aqueous sodium hydroxide solution and extracted threetimes with diethylether (100 mL each).

The combined organic phases were concentrated to a volume ofapproximately 80 mL and 50 mL of 2N aqueous hydrochloric acid wereadded. The biphasic system was stirred vigourously at room temperaturefor 3 h. The phases were separated, the aqueous layer was adjusted to pH12 by addition of 5N sodium hydroxide solution and extracted three timeswith a 3:1 mixture of dichloromethane and 2-propanol (80 mL each). Thecombined organic layers were evaporated to give 92 mg of the desiredproduct, which was used directly in the next step. R_(t)=0.64 min(Method 18). Detected mass: 252.2 (M+H⁺).

cis-4-(2-Amino-butyl)-4-(4-fluoro-phenyl)-cyclohexanol (94)

355 mg of cis-4-(2-Amino-butyl)-4-(4-fluoro-phenyl)-cyclohexanol (94)were prepared analoguosly to the preparation ofcis-4-(2-amino-propyl)-4-(4-fluoro-phenyl)-cyclohexanol (93), startingfrom 500 mg (1.44 mmol) ofcis-[4-(tert-butyl-dimethyl-silanyloxy)-1-(4-fluoro-phenyl)-cyclohexyl]acetonitrile(92), 960 μL (2.88 mmol) of ethylmagnesium bromide (3M in diethylether)and 54.4 mg (2.88 mmol) of sodium borohydride. R_(t)=0.66 min (Method18). Detected mass: 266.2 (M+H⁺).

Example 109cis-6-[4-(2-Amino-propyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one

Example 109 was synthesized using the reaction sequence as described forthe synthesis of Example 1. 90 mg ofcis-4-(2-amino-propyl)-4-(4-fluoro-phenyl)-cyclohexanol (93) and 79.6 mgof 7-chloro-6-fluoro-1-methoxy-isoquinoline (10) were used to give 35 mgof Example 109 as hydrochloride. R_(t)=1.31 min (Method 16). Detectedmass: 429.2 (M+H⁺).

Example 110cis-6-[4-(2-Amino-butyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one

Example 110 was obtained as hydrochloride following the reactionsequence as used for the synthesis of Example 109, starting fromcis-4-(2-amino-butyl)-4-(4-fluoro-phenyl)-cyclohexanol (94) and7-chloro-6-fluoro-1-methoxy-isoquinoline (10). R_(t)=1.45 min (Method16). Detected mass: 443.2 (M+H⁺).

tert-Butyl-(7-chloro-6-fluoro-isoquinolin-1-yl)-amine (95)

A solution of 5.0 g (25.3 mmol) of7-chloro-6-fluoro-isoquinoline-2-oxide (9) in 120 mL of benzotrifluoridewas treated with 15.9 mL (11.1 g, 152 mmol) of tert-butylamine andcooled to 0° C. Then, 17.3 g (53.1 mmol) of p-toluenesulfonic anhydridewere added portionwise with temperature control (<10° C.). The reactionmixture was stirred at room temperature for 16 h, before being cooled to0° C. and another 8.0 mL (76.1 mmol) of tert-butylamine and 8.26 g (25.3mmol) of p-toluenesulfonic anhydride were added. The reaction mixturewas stirred for 24 h at room temperature, then concentrated andpartitioned between 120 mL of water and 150 mL of dichloromethane. Thephases were separated and the organic phase was washed eight times with3N aqueous sodium hydroxide, to extract excess p-toluenesulfonic acid,dried over magnesium sulphate, filtered and evaporated to dryness. Thecrude product was purified twice by silica gel chromatography(dichloromethane:methanol) to give 277 mg of pure desired product (95)and 714 mg of the product slightly contaminated with p-toluenesulfonicacid. R_(t)=2.35 min (Method 2). Detected mass: 253.1 (M+H⁺).

Example 111cis-6-[4-(1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-isoquinolin-1-ylamine

58 mg of Example 111 were obtained following a reaction sequence withNaH-mediated coupling and acidic deprotection in the microwave similarto the one used for the synthesis of Example 1, starting from 102 mg(0.44 mmol) of cis-4-(1-aminopropyl)-4-phenylcyclohexanol (6) and 100 mg(0.40 mmol) of tert-butyl-(7-chloro-6-fluoro-isoquinolin-1-yl)-amine(95). R_(t)=0.84 min (Method 11). Detected mass: 410.3 (M+H⁺).

{1-[8-(4-Methoxy-phenyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-propyl}-carbamicacid benzyl ester (96)

5.0 g (18.3 mmol) of8-(4-methoxy-phenyl)-1,4-dioxa-spiro[4.5]decane-8-carbonitrile(synthesized from 1-(4-methoxy-phenyl)-4-oxo-cyclohexanecarbonitrile ina similar fashion as described for 15) were dissolved in 20 mL ofabsolute toluene. Then, 12.2 mL (36.6 mmol) of ethylmagnesium chloride(3M in THF) were added dropwise and the reaction mixture was heated to90° C. for 5 h. After cooling to −15° C., 10 mL of dry methanol wereadded. After a period of 10 min, 1.37 g (36.3 mmol) of sodiumborohydride were added portionwise at 0° C. and the mixture was stirredfor 16 h at room temperature. The reaction was quenched by addition of1M aqueous sodium hydroxide solution (100 mL) and extracted three timeswith diethylether (150 mL each). The combined organic phases were driedover magnesium sulphate, filtered and the solvent evaporated.

The crude amine (4.90 g) was dissolved in 55 mL of dry dichloromethane,cooled to −78° C. and 2.46 mL (1.79 g, 17.6 mmol) of triethylamine and2.71 mL (2.74 g, 16.0 mmol) of benzylchloroformate were added. Thereaction mixture was warmed to room temperature and stirred for 2 h.Then, 100 mL of water were added and the mixture was extracted threetimes with ethyl acetate. The combined organic phases were dried overmagnesium sulphate, filtered and concentrated to give the crude product(96), which was used directly in the next step. R_(t)=1.09 min (Method18). Detected mass: 440.4 (M+H⁺).

{1-[1-(4-Methoxy-phenyl)-4-oxo-cyclohexyl]-propyl}-carbamic acid benzylester (97)

534 mg of{1-[8-(4-Methoxy-phenyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-propyl}-carbamicacid benzyl ester (96) were dissolved in 1 mL of a 2:1 mixture ofacetone and 6N aqueous hydrochloric acid. The reaction mixture wasstirred for 16 h at room temperature, then dropped into 150 mL ofsaturated aqueous sodium bicarbonate solution. The phases were separatedand the aqueous phase was extracted three times with dichloromethane(100 mL each). The combined organic phases were dried over magnesiumsulphate, filtered and concentrated to give the ketone 97. R_(t)=1.58min (Method 19). Detected mass: 396.3 (M+H⁺).

{1-[4-Amino-1-(4-methoxy-phenyl)-cyclohexyl]-propyl}carbamic acid benzylester (98)

200 mg (0.51 mmol) of the ketone (97) were dissolved in 1.5 mL ofabsolute methanol, then 390 mg (5.06 mmol) of ammonium acetate and 31.8mg (0.51 mmol) of sodium cyanoborohydride were added, and the mixturewas stirred at room temperature for 2 h. The reaction mixture wasevaporated, the residue dissolved in 50 mL of 1N aqueous sodiumhydroxide and extracted twice with 100 mL of dichloromethane. Thecombined organic layer was dried over magnesium sulphate, filtered, andevaporated to give 150 mg of the title compound 98 in a puritysufficient to be used directly in the next step. R_(t)=1.18 min (Method19). Detected mass: 397.3 (M+H⁺).

{1-[4-(Isoquinolin-6-ylamino)-1-(4-methoxy-phenyl)-cyclohexyl]-propyl}-carbamicacid benzyl ester (99)

In 1 mL of absolute toluene were dissolved 66.0 mg (0.32 mmol) of6-bromo-isoquinoline, 151 mg (380 μmol) of{1-[4-amino-1-(4-methoxy-phenyl)-cyclohexyl]-propyl}-carbamic acidbenzyl ester (98), and 155 mg (476 μmol) of cesium carbonate. Thesolution was degassed twice, then 2.14 mg (9.5 μmol) of palladiumacetate and 8.89 mg (14.3 μmol) of2,2′-bis(diphenylphosphino)-1,1′-binaphthyl were added and the reactionmixture was heated to 100° C. until complete conversion could beobserved. The mixture was evaporated, then redissolved in 50 mL ofdichloromethane and washed twice with 50 mL of saturated aqueous sodiumbicarbonate solution. The organic phase was dried over magnesiumsulphate, filtered, concentrated and purified by silica gelchromatography (dichloromethane:methanol) to give 48 mg of the puredesired product. R_(t)=1.38 min (Method 19). Detected mass: 524.4(M+H⁺).

Example 112[4-(1-Amino-propyl)-4-(4-methoxy-phenyl)-cyclohexyl]-isoquinolin-6-yl-amine

48 mg (91.7 μmol) of{1-[4-(Isoquinolin-6-ylamino)-1-(4-methoxy-phenyl)-cyclohexyl]-propyl}-carbamicacid benzyl ester (99) were dissolved in 300 μL of dry methanol and 9.7μg of palladium on activated charcoal (10%) were added. The mixture wasstirred under a hydrogen atmosphere until conversion was complete. Thecatalyst was filtered off and the reaction mixture was evaporated todryness to give the title compound. R_(t)=0.89 min (Method 19). Detectedmass: 390.3 (M+H⁺).

1-(Di-tert-butyloxycarbonyl)-amino-[4-(1-amino-propyl)-4-(4-methoxy-phenyl)-cyclohexyl]-isoquinolin-6-yl-amine(100)

30 mg (83.5 μmol) of1-(di-tert-butyloxycarbonyl)-amino-isoquinolin-6-amine were dissolved in135 μL of abs. methanol, then 23 μL (16.9 mg, 167 μmol) oftriethylamine, 47.7 μL (50.1 mg, 835 μmol) of acetic acid, 20 mg ofpowdered molecular sieves and 99 mg (250 μmol) of (97) were added andthe mixture was allowed to stir for 1 h. A solution of 15.7 mg (250μmol) of sodium cyanoborohydride in 50 μL of methanol was added and themixture was stirred at 70° C. for 10 h. Then, another 50 mg (125 μmol)of (97) followed by a portion of 15.7 mg (250 μmol) of sodiumcyanoborohydride in 50 μL of methanol were added and the mixture wasallowed to stir for 1 h at 70° C. The reaction mixture was filtered andthe filtrate was evaporated to dryness. The residue was dissolved in 50mL of dichloromethane and washed with saturated sodium bicarbonatesolution. The aqueous phase was reextracted three times withdichloromethane. The combined organic layer was dried over magnesiumsulphate, filtered, evaporated and the crude material was purified byreversed phase HPLC (acetonitrile/water) to yield 5 mg of the desiredproduct as trifluoroacetic acid salt. R_(t)=1.65 min (Method 19).Detected mass: 739.3 (M+H⁺).

Example 1131-Amino-[4-(1-amino-propyl)-4-(4-methoxy-phenyl)-cyclohexyl]-isoquinolin-6-yl-amine

5 mg (6.77 μmol) of1-(Di-tert-butyloxycarbonyl)-amino-[4-(1-amino-propyl)-4-(4-methoxy-phenyl)-cyclohexyl]-isoquinolin-6-yl-amine(100) were dissolved in 500 μL of dry methanol and 5.0 mg of palladiumon activated charcoal (10%) were added. The mixture was stirred under ahydrogen atmosphere until conversion was complete. The catalyst wasfiltered off and the reaction mixture was evaporated to dryness. Thesolid residue was treated with 500 μL of 4N hydrochloric acid in dioxaneand stirred at room temperature until complete deprotection could beobserved. The reaction mixture was evaporated, water was added and themixture was lyophilized. The residue was taken up in water andlyophilized again to give 1.2 mg of the desired product ashydrochloride. Rt=0.98 min (Method 19). Detected mass: 405.3 (M+H⁺).

cis-2-Methyl-propane-2-sulfinic acid1-[4-(tert-butyl-dimethyl-silanyloxy)-1-(4-fluoro-phenyl)-cyclohexyl]-methylideneamide(101)

To a solution of 3.0 g (8.92 mmol) ofcis-4-(tert-butyl-dimethyl-silanyloxy)-1-(4-fluoro-phenyl)-cyclohexanecarbaldehyde(91) in 26 mL of tetrahydrofuran were added 1.19 g (9.81 mmol) of2-methyl-2-propanesulfinamide and 4.31 mL (4.69 g, 13.4 mmol) oftitanium(IV) ethoxide. The resulting mixture was stirred for 16 h underreflux, before being treated with 30 mL of water. The resultingsuspension was filtered through celite. The filter cake was rinsed with200 mL of ethyl acetate and 60 mL of water. The phases were separatedand the aqueous layer was extracted with ethyl acetate. The combinedorganic layers were dried over magnesium sulphate, filtered, andconcentrated in vacuo. The crude product was purified by flashchromatography (SiO₂, 0%→100% ethyl acetate in heptane) to yield 1.64 gof the title compound (101). R_(t)=1.15 min (Method 17). Detected mass:440.2 (M+H⁺).

cis-2-Methyl-propane-2-sulfinic acid{2-benzenesulfonyl-1-[4-(tert-butyl-dimethyl-silanyloxy)-1-(4-fluoro-phenyl)-cyclohexyl]-2-fluoro-ethyl}-amide(102)

A solution of 1.75 g (3.98 mmol) of cis-2-methyl-propane-2-sulfinic acid1-[4-(tert-butyl-dimethyl-silanyloxy)-1-(4-fluoro-phenyl)-cyclohexyl]-methylideneamide(101) and 693 mg (3.98 mmol) of fluoromethyl-phenyl-sulfone in 40 mL ofdry tetrahydrofuran was cooled to −78° C. and 4.17 mL (4.17 mmol) of a1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran wereadded. The mixture was stirred for 1 h at −78° C. before being quenchedby addition of saturated aqueous ammonium chloride solution andextracted twice with ethyl acetate. The combined organic layers weredried over magnesium sulphate, filtered, and concentrated in vacuo togive 2.45 g of the crude title compound (102) as diastereomeric mixture.R_(t)=3.31 min (Method 12). Detected mass: 614.3 (M+H⁺)

cis-2-Methyl-propane-2-sulfinic acid{1-[4-(tert-butyl-dimethyl-silanyloxy)-1-(4-fluoro-phenyl)-cyclohexyl]-2-fluoro-ethyl}-amide(103)

1.70 g (2.77 mmol) of cis-2-Methyl-propane-2-sulfinic acid{2-benzenesulfonyl-1-[4-(tert-butyl-dimethyl-silanyloxy)-1-(4-fluoro-phenyl)-cyclohexyl]-2-fluoro-ethyl}-amide(102) was dissolved in 30 mL of dry methanol and 1.57 g (11.1 mmol) ofdibasic sodium phosphate were added. The suspension was cooled to −20°C., and treated with 2.48 g of sodium mercury amalgam (5% mercury). Thereaction mixture was stirred at 0° C. for 16 h and another 620 mg ofsodium amalgam were added. After stirring for 24 h at room temperature,the solution was decanted from the solids, evaporated to dryness and theresidue partitioned between 50 mL of brine and 100 mL of diethylether.The organic layer was dried over sodium sulphate, filtered andconcentrated in vacuo. Purification by flash chromatography (SiO₂,0%→100% ethyl acetate in heptane) yielded 300 mg of the title compound(103). R_(t)=1.07 min (Method 17). Detected mass: 474.4 (M+H⁺).

cis-4-(1-Amino-2-fluoro-ethyl)-4-(4-fluoro-phenyl)cyclohexanol (104)

A solution of 300 mg (0.63 mmol) of cis-2-methyl-propane-2-sulfinic acid{1-[4-(tert-butyl-dimethyl-silanyloxy)-1-(4-fluoro-phenyl)-cyclohexyl]-2-fluoro-ethyl}-amide(103) in 3 mL of 2-propanol was treated with 3 mL of 6N aqueoushydrochloric acid and stirred for 18 h at room temperature. The mixturewas washed with 50 mL of diethylether and lyophilized, then taken up inwater and lyophilized again to give the title compound (104) as itshydrochloride. R_(t)=0.49 min (Method 18). Detected mass: 256.3 (M+H⁺).

Example 114cis-6-[4-(1-Amino-2-fluoro-ethyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one

Example 114 was synthesized using the reaction sequence as described forthe synthesis of Example 1. 209 mg ofcis-4-(1-amino-2-fluoro-ethyl)-4-(4-fluoro-phenyl)-cyclohexanol (104)and 158 mg of 7-chloro-6-fluoro-1-methoxy-isoquinoline (10) were used togive 132 mg of Example 114 as its hydrochloride. R_(t)=1.79 min (Method12). Detected mass: 433.2 (M+H⁺)

2-Methyl-propane-2-sulfinic acid8-(4-fluoro-phenyl)-1,4-dioxa-spiro[4.5]dec-8-ylmethyleneamide (105)

To a solution of 10.0 g (38.3 mmol) of8-(4-fluoro-phenyl)-1,4-dioxa-spiro[4.5]decane-8-carbonitrile (15) in 44mL of tetrahydrofuran at −78° C. were slowly added 76.5 mL (76.5 mmol)of a 1M solution of diisobutylaluminium hydride in toluene and thereaction was allowed to warmed to 0° C. over a period of 3 h. Themixture was recooled to −78° C., neutralized by dropwise addition of a10% aqueous citric acid solution and warmed to room temperature over 15h. The mixture was extracted three times with methyl-tert.butyl ether(50 mL each), the combined organics were dried over magnesium sulphate,filtered and evaporated to give8-(4-fluoro-phenyl)-1,4-dioxa-spiro[4.5]decane-8-carbaldehydecarbaldehyde.

The crude aldehyde was dissolved in 113 mL of tetrahydrofuran and 5.09 g(42.0 mmol) of 2-methyl-2-propanesulfinamide and 12.0 mL (13.1 g, 57.3mmol) of titanium(IV) ethoxide were added. The resulting mixture wasstirred for 3 h under reflux and 16 h at room temperature, before beingtreated with 30 mL of water and filtered through celite. The filter cakewas washed with 200 mL of ethyl acetate and 60 mL of water, the phaseswere separated and the aqueous layer was extracted twice with ethylacetate. The combined organic layers were dried over magnesium sulphate,filtered, and concentrated in vacuo. The crude product was purified byflash chromatography (SiO₂, 0%→100% ethyl acetate in heptane) to yield3.20 g of the title compound (105). R_(t)=1.01 min (Method 18). Detectedmass: 368.3 (M+H⁺).

2-Methyl-propane-2-sulfinic acid{1-[8-(4-fluoro-phenyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-allyl}-amide (106)

Under argon, 2.00 g (5.44 mmol) of 2-methyl-propane-2-sulfinic acid8-(4-fluoro-phenyl)-1,4-dioxa-spiro[4.5]dec-8-ylmethyleneamide (105)were dissolved in 27 mL of absolute tetrahydrofuran. Then, 5.99 mL (5.99mmol) of vinylmagnesium bromide (1M in tetrahydrofuran) were addeddropwise at 0° C. and the reaction mixture was stirred for 17 h at roomtemperature. Another 3 mL (3.00 mmol) of vinylmagnesium bromide (1M intetrahydrofuran) were added and the mixture stirred for 20 h at roomtemperature. The reaction mixture was cooled to 0° C. and 15 mL ofsaturated aqueous sodium sulphate solution were added. The suspensionwas filtered over celite, the organic layer was dried over magnesiumsulphate, filtered, and concentrated in vacuo. The crude product waspurified by flash chromatography (SiO₂, 0%→100% ethyl acetate inheptane) to yield 1.09 g of (106). R_(t)=0.96 min (Method 18). Detectedmass: 396.4 (M+H⁺).

2-Methyl-propane-2-sulfinic acid{1-[8-(4-fluoro-phenyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-3-methoxy-propyl}-amide(107)

16.5 mL (8.23 mmol) of a 0.5M solution of 9-BBN in tetrahydrofuran wereadded to a solution of 1.09 g (2.74 mmol) of 2-methyl-propane-2-sulfinicacid {1-[8-(4-fluoro-phenyl)-1,4-dioxa-spiro[4.5]dec-8-yl]allyl}-amide(106) in 5 mL THF at 0° C. The reaction mixture was allowed to warm toroom temperature over night, before being cooled to 0° C. Then, 20 mL of3M aqueous sodium hydroxide and 7.5 mL of 30% aqueous hydrogen peroxidewere added slowly, and the mixture was stirred for 16 h at roomtemperature. The mixture was extracted twice with 50 mL of ethylacetate, washed with water and saturated sodium chloride solution, driedover magnesium sulfate and concentrated in vacuo. The crude alcohol wasdissolved in 5 mL of tetrahydrofuran and added slowly to a suspension of131 mg (4.46 mmol) of sodium hydride (60%) in 5 mL tetrahydrofuran at 0°C. 515 μL (8.20 mmol) of iodomethane were added, and after stirring for16 h at room temperature another 50 mg of sodium hydride (60%) wereadded. The reaction mixture was stirred for 1 h at room temperature,then 30 mL of methanol and 15 mL of aqueous ammonium hydroxide solution(33%) were added. The reaction mixture was evaporated to dryness andlyophilized from water to give 1.17 g of the title compound (107) in apurity sufficient for further conversion. R_(t)=0.93 min (Method 18).Detected mass: 428.2 (M+H⁺).

cis-4-(1-Amino-3-methoxy-propyl)-4-(4-fluoro-phenyl)-cyclohexanol (108)

A solution of 1.16 g (2.71 mmol) of 2-methyl-propane-2-sulfinic acid{1-[8-(4-fluoro-phenyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-3-methoxy-propyl}-amide(107) in a mixture of 5 mL of acetic acid and 1.25 mL of water washeated in the microwave oven at 100° C. for 5 min. The mixture wascooled to room temperature and slowly poured onto 100 mL of coldsaturated aqueous sodium bicarbonate solution. The mixture was extractedthree times with a 3:1 mixture of dichloromethane and ethanol (50 mLeach). The organic phase was concentrated in vacuo to remove thedichloromethane and 203 mg (5.37 mmol) of sodium borohydride were added.The reaction mixture was stirred at room temperature overnight, whenanother 203 mg (5.37 mmol) of sodium borohydride were added. After 18 hat room temperature, the reaction mixture was quenched with water,concentrated in vacuo and lyophilized twice from water to give the titlecompound (108), which was used crude in the next step. R_(t)=1.95 min(Method 2). Detected mass: 282.2 (M+H⁺).

Example 115cis-6-[4-(1-Amino-3-methoxy-propyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one

Example 115 was synthesized using the reaction sequence as described forthe synthesis of Example 1. 414 mg ofcis-4-(1-amino-3-methoxy-propyl)-4-(4-fluoro-phenyl)-cyclohexanol (108)and 283 mg of 7-chloro-6-fluoro-1-methoxy-isoquinoline (10) were used togive 66.6 mg of Example 115 as its hydrochloride. R_(t)=1.88 min (Method12). Detected mass: 459.3 (M+H⁺)

1-(1,4-Dioxa-spiro[4.5]dec-8-yl)-1-phenyl-ethylamine (26)

Under argon, phenylmagnesium bromide (3M) in diethyl ether (6.7 mL, 20mmol) was added to a solution of1,4-dioxa-spiro[4.5]decane-8-carbonitrile (3.34 g, 20 mmol) in diethylether (60 mL). The mixture was stirred for 30 minutes. Titanium (IV)isopropoxide (5.7 g, 20 mmol) was then added. After stirring for 5 min,methyl lithium (1.6 M in diethyl ether, 31.2 mL, 50 mmol) was added andthe reaction was heated under reflux for 10 hours. After cooling inice/water the brown mixture was treated cautiously with 2M NaOH solution(30 mL) dropwise (exothermic). The mixture was extracted with t-butylmethyl ether and dried over sodium sulphate. After filtration theorganic phase was evaporated to give 5 g of a pale yellow oil, which wasused in the next step without further purification. R_(t)=2.10 min(Method 2). Detected mass: 261.2 (M+H⁺).

4-(1-Amino-1-phenyl-ethyl)-cyclohexanone (27)

Crude 1-(1,4-dioxa-spiro[4.5]dec-8-yl)-1-phenyl-ethylamine (26, 2.5 g)was dissolved in acetone (40 mL) and treated with 6M aqueoushydrochloric acid (21.1 mL). After 5 hours stirring the mixture wasevaporated at less than 20° C. to give a residue which was treated withdichloromethane, washed with saturated sodium bicarbonate solution,dried and filtered to give a solution of crude product which was usedimmediately. R_(t)=0.7 min (Method 5). Detected mass: 218.3 (M+H⁺).

[1-(4-Oxo-cyclohexyl)-1-phenyl-ethyl]carbamic acid tert-butyl ester (28)

With cooling di-tert.-butyl dicarbonate (3.46 g, 10.6 mmol) andtriethylamine (1.47 mL, 10.6 mmol) was added to the crude solution of4-(1-amino-1-phenyl-ethyl)-cyclohexanone (27) from the previous stage.After stirring overnight, the reaction was worked up by extraction withdichloromethane, washing with 1M NaOH solution and then with 0.05Maqueous hydrochloric acid (three times until pH of washings were pH4).After washing the organic phase with brine, it was dried over sodiumsulphate, filtered and evaporated to give crude product (28) as acolourless oil which was used without further purification. R_(t)=0.14min (Method 5). Detected mass: 318.4 (M+H⁺)

[1-(4-Hydroxy-cyclohexyl)-1-phenyl-ethyl]carbamic acid tert-butyl ester(29)

[1-(4-Oxo-cyclohexyl)-1-phenyl-ethyl]-carbamic acid tert-butyl ester(28) from the previous stage (2.7 g) was dissolved in THF (60 mL) andcooled to −70° C. Sodium borohydride was added (356 mg) and the reactionmixture stirred overnight with gradual warming to room temperature.Water was added and the solution extracted with t-butylmethyl ether. Theorganic phase was washed with brine and dried over sodium sulphate.Evaporation gave 1.24 g of a white foam as crude product. R_(t)=1.41 min(Method 5). Detected mass: 246.3 (M—C₄H₈—H₂O+H⁺).

4-(1-Amino-1-phenyl-ethyl)-cyclohexanol (30)

Trifluoroacetic acid (8 mL) was added to a solution of[1-(4-hydroxy-cyclohexyl)-1-phenyl-ethyl]-carbamic acid tert-butyl ester(29) in dichloromethane (75 mL) from the previous stage. After stirringfor 4 hours the reaction mixture was worked up by adding 2M aqueoushydrochloric acid (39 mL), followed by evaporation. Freeze dryingovernight gave a pale brown semi-solid residue. This was treated with amixture of water and acetonitrile. After freeze drying again 1.24 g ofcrude product as the hydrochloride was obtained which was used in thenext stage without further purification. R_(t)=0.58 min (Method 5).Detected mass: 185.15 (M—NH₃—H₂O+H⁺).

1-[4-(1-Benzyloxy-7-chloro-isoquinolin-6-yloxy)-cyclohexyl]-1-phenyl-ethylamine(31)

4-(1-Amino-1-phenyl-ethyl)-cyclohexanol (30, 404 mg, 1.6 mmol) wasevaporated twice to dryness from toluene. The residue was dissolved indimethylacetamide (3 mL) and the solution added dropwise to a suspensionof sodium hydride (114 mg, 4.1 mmol, 60% in mineral oil) in dimethylacetamide (8 mL) under argon. After stirring for 1 hour, a solution of1-benzyloxy-7-chloro-6-fluoroquinoline (38, 0.31 g, 1.09 mmol) indimethylacetamide (6 mL) was added dropwise and the mixture stirredovernight. Then mixture was then heated and stirred at 60° C. for 1 hourbefore cooling and addition of water (30 mL) to quench the reaction. Theproduct was isolated by extraction with dichloromethane/isopropanol(3:1) and evaporation of the organic phase under reduced pressure.Purification by column chromatography (silica gel, 2% methanol indichloromethane) gave the desired product (67 mg) as a colourless solid.R_(t)=4.3 min (Method 3). Detected mass: 487.3 (M+H⁺).

Example 346-[4-(1-Amino-1-phenyl-ethyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one

Hydrochloric acid (6.6 mL of a 2M aqueous solution) was added to asolution of1-[4-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-cyclohexyl]-1-phenyl-ethylamine(31, 67 mg, 0.14 mmol) in isopropanol (7 mL). The reaction mixture wasstirred overnight. Isopropanol was removed under reduced pressure andthe remaining aqueous solution freeze dried to give crude product as anamorphous powder.

This was treated twice with acetonitrile/water and freeze dried to give57 mg of the desired product as a colourless hydrochloride salt.R_(t)=2.83 min (Method 3). Detected mass: 380.3 (M—NH₃+H⁺).

Example 1166-{4-[1-Amino-1-(4-fluoro-phenyl)-ethyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one(Isomer 1)

6-{-4-[1-Amino-1-(4-fluoro-phenyl)-ethyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one(Example 116) was obtained by the same procedure described for thesynthesis of Example 34 using 1-benzyloxy-7-chloro-6-fluoroquinoline(38) and 4-[amino-4-fluoro-phenyl-methyl]-cyclohexanol (prepared from1,4-dioxa-spiro[4.5]decane-8-carbonitrile, 4-fluorophenyl-magnesiumbromide and methyl lithium analogously to 30). R_(t)=1.74 min (Method20). Detected mass: 398.2 (M—NH₃+H⁺).

Example 1176-{-4-[1-Amino-1-(4-methoxy-phenyl)-ethyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-onea)1-[4-(7-chloro-1-methoxyisoquinolin-6-yloxy)-cyclohexyl]-1-(4-methoxyphenyl)-ethylamine(109)

4-[1-Amino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol (prepared asdescribed for the synthesis of 30, 400 mg, 1.4 mmol) was evaporatedtwice to dryness from toluene. The residue was dissolved indimethylacetamide (3 mL) and the solution added dropwise to a suspensionof sodium hydride (147 mg, 3.7 mmol, 60% in mineral oil) in dimethylacetamide (6 mL) under argon. After stirring for 1 hour, a solution of7-chloro-6-fluoro-1-methoxyisoquinoline (0.3 g, 1.4 mmol) indimethylacetamide (6 mL) was then added dropwise and the mixture stirredovernight. The mixture was then heated and stirred at 60° C. for 1 hourbefore cooling and addition of water (30 mL) to quench the reaction.

Product was isolated by extraction with dichloromethane/isopropanol(3:1) and evaporation of the organic phase under reduced pressure.Purification by column chromatography (silica gel, dichloromethane todichloromethane:methanol=98:2 to MeOH) gave desired product (30 mg) as acolourless solid. R_(t)=3.84 min (Method 3). Detected mass: 441.4(M+H⁺).

b)6-{4-[1-Amino-1-(4-methoxy-phenyl)-ethyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one(Example 117)

Hydrochloric acid (0.4 mL of a 1M aqueous solution) was added to asolution of1-[4-(7-chloro-1-methoxyisoquinolin-6-yloxy)-cyclohexyl]-1-(4-methoxyphenyl)-ethylamine(109, 30 mg, 0.07 mmol) in isopropanol (0.4 mL). The reaction mixturewas heated in a microwave oven at 100° C. for 30 minutes. Isopropanolwas removed under reduced pressure and the remaining aqueous solutionfreeze dried to give crude product as an amorphous powder. This wastreated twice with acetonitrile/water and freeze dried to give 29 mg ofthe desired product Example 117 as a colourless hydrochloride salt.R_(t)=2.60 min (Method 2). Detected mass: 410.1 (M—NH₃+H⁺).

The following racemic products were obtained by the same proceduredescribed for the synthesis of Example 117 using7-chloro-6-fluoro-1-methoxyisoquinoline (10) and the correspondingaminoalcohols (prepared from the respective carbonitriles, grignardreagents and methyl or ethyl lithium reagents analogously to 30). Onestereoisomer could be isolated (named isomer 1); the relativestereochemistry was not assigned.

Exam Chemical R_(t)/ ple Product Name [M + H⁺] [min] Method 118

6-{4-[1-Amino- 1-cyclopentyl- ethyl]-cyclo- hexyl-oxy}-7- chloro-2H-iso-quinolin-1-one 389.5 3.10  3 119

6-{4-[1-Amino- 1-ethyl-propyl]- cyclohexyloxy}- 7-chloro-2H-isoquinolin-1- one 363.2 1.71 12 120

6-{4-[1-Amino- 1-cyclopropyl- ethyl]-cyclo- hexyloxy}-7- chloro-2H-iso-quinolin-1-one 361.2 1.98 13 121

6-{4-[1-Amino- 1-n-propyl- ethyl]-cyclo hexyloxy}-7- chloro-2H-isoquinolin-1- one 363.2 1.77 12

Example 1226-{-4-[1-Amino-1-ethyl-propyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one(Isomer 2) a) 7-chloro-6-hydroxy-1-methoxyisoquinoline (110)

A solution of sodium trimethylsilanoate (149.2 mL, 1M in THF) was addedto a solution of 7-chloro-6-fluoro-1-methoxyisoquinoline (10, 10 g, 47.2mmol) in DMA (200 mL) under argon. After stirring at 60° C. for 24hours, the solution was evaporated under reduced pressure and thenfreeze dried to give crude product (20.4 g). This was dissolved in waterand the pH adjusted to pH=6.5. A light brown precipitate was collectedby filtration and purified by reverse phase chromatography (0 to 4minutes, 15% acetonitrile/water, 4 to 24 minutes 15 to 90%acetonitrile/water and then 100% acetonitrile) to give 7 g of thedesired product. R_(t)=2.60 min (Method 2). Detected mass: 210.0 (M+H⁺).

b)1-(4-[7-Chloro-1-methoxyisoquinolin-6-yloxy-cyclohexyl)-1-ethyl-propyl]-carbamicacid tert-butyl ester (111)

[1-(4-Hydroxycyclohexyl)-1-ethyl-propyl]-carbamic acid tert-butyl ester(from the preparation of 119) was dried by evaporating twice fromtoluene. The dried material was dissolved in dry THF (2.5 mL) andtriphenylphosphine (0.63 g, 2.42 mmol), and7-chloro-6-hydroxy-1-methoxyisoquinoline (110, 0.39 g, 1.86 mmol) added.Then Hunig's base (0.24 g, 0.32 mL, 1.86 mmol) was added. The reactionmixture was cooled to 0° C. and DEAD (0.49 g, 434 μl, 2.79 mmol) addeddropwise over 1 hour. The reaction mixture was warmed to 25° C. andstirred overnight.

The reaction mixture was taken up in dichloromethane, washed twice withaqueous 2M NaOH solution and once with brine. Drying over sodiumsulphate followed by filtration and evaporation gave 1.7 g of crudeproduct which was purified by stirring three times with 5% ethylacetate/95% heptane. Combined organic extracts were evaporated to give abrown residue which was purified by chromatography on silica gel.Elution with heptane/ethyl acetate (95:5) gave 113 mg of desiredcompound. R_(t)=1.54 min (Method 11). Detected mass: 476.2 (M+H⁺).

c)6-{-4-[1-Amino-1-ethyl-propyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,isomer 2 (Example 122)

1-(4-[7-Chloro-1-methoxyisoquinolin-6-yloxy-cyclohexyl)-1-ethyl-propyl]-carbamicacid tert-butyl ester (111, 113 mg, 0.24 mmol) was dissolved inisopropanol (1.5 mL) and treated with hydrochloric acid (1M, 1.5 mL).The reaction mixture was heated in a microwave oven at 100° C. for 30minutes. Evaporation gave crude product, which was treated twice withacetonitrile/water and freeze dried to give 63 mg of the desired productas a colourless hydrochloride salt. R_(t)=2.45 min (Method 2). Detectedmass: 363.3 (M+H⁺).

The following two racemic products were obtained by the same proceduredescribed for the synthesis of Example 122 using7-chloro-6-hydroxy-1-methoxyisoquinoline (110) and the corresponding1-(4-hydroxycyclohexyl)-1-ethyl]-carbamic acid tert-butyl ester(prepared analogously to 30). The isolated products are differentstereoisomers as compared to Example 34 and Example 121, therefore named“isomer 2”, their relative stereochemistry, however, was not assigned.

Exam- R_(t)/ Meth ple Product Chemical Name [M + H⁺] [min] od 123

6-{4-[1-Amino- 1-phenyl-ethyl]- cyclohexyloxy}- 7-chloro-2H-isoquinolin-1- one 397.12 1.74 12 124

6-{4-[1-Amino- 1-methyl-n- butyl]-cyclo hexyloxy}-7- chloro-2H-isoquinolin-1- one 363.2 1.76 21

Example 125 and 1266-[3-(1-Amino-propyl)-3-(4-fluoro-phenyl)-cyclobutyloxy]-7-chloro-2H-isoquinolin-1-onea) 3-Cyano-3-(4-fluorophenyl)cyclobutan-1-ol (112)

Methyl lithium-lithium bromide complex (123 mL, 185 mmol) was addeddropwise to a solution of 4-fluoroacetonitrile (22 mL, 25 g, 185 mmol)in THF (550 mL) at −70° C. After stirring for 1 hour at −70° C., asolution of epibromhydrin (15.8 mL, 25.3 g, 185 mmol) in THF (125 mL)was added dropwise. The reaction mixture was stirred for a further hour.Then, at −70° C., methyl magnesium iodide in ether (3M, 61.7 mL, 185mmol) was added dropwise and the reaction mixture allowed to warm upgently to room temperature with stirring overnight. The reaction mixturewas then cooled in an ice bath and dropwise water (30 mL) and thenhydrochloric acid (5M) were added. The acidic solution was saturatedwith sodium chloride and extracted with methyl t-butyl ether. Theorganic phase was then washed with sodium thiosulphate solution andbrine. After drying over sodium sulphate, followed by filtration, thesolvent was removed under reduced pressure to give crude product (33.5g) as an orange oil. The compound was purified by chromatography onsilica gel, elution with heptane/ethyl acetate gave 19.8 g of thedesired compound. R_(t)=3.33 min (Method 3). Detected mass: 192.1(M+H⁺).

b) 3-Cyano-3-(4-fluorophenyl)cyclobutan-1-yl t-butyldimethylsilyl ether(113)

3-cyano-3-(4-fluorophenyl)cyclobutan-1-ol (112, 19.8 g, 103.6 mmol) wasdissolved in dichloromethane (200 mL) under argon, then 2,6-lutidine(27.78 g, 30.1 mL, 259 mmol) was added and the solution cooled to 0° C.tert-Butyldimethylsilyl trifluoromethanesulphonate (32.9 g, 28.6 mL,124.3 mmol) was added dropwise and the stirred reaction mixture was thenallowed to warm up to room temperature overnight. The reaction mixturewas washed successively with water, hydrochloric acid (0.1M), saturatedsodium bicarbonate solution and brine before being dried over sodiumsulphate. Filtration and evaporation gave 32.9 g of a yellow oil whichwas used in the next step without further purification. R_(t)=1.30 min(Method 18). Detected mass: 306.3 (M+H⁺).

c) 1-(1-Aminopropyl)-1-(4-fluorophenyl)cyclobutan-3-ol (114)

3-cyano-3-(4-fluorophenyl)cyclobutan-1-yl-t-butyldimethylsilyl ether(113, 1.55 g, 5.1 mmol) was dissolved in toluene (4 mL) and ethylmagnesium bromide (3.4 mL, 10.2 mmol, 3M in ether) added dropwise. Thereaction mixture was then stirred for 30 minutes at 90° C. After coolingto 0° C., the reaction was quenched by addition of methanol (20 mL)followed by addition of sodium borohydride (384 mg, 10.2 mmol). Afterstirring overnight dilute sodium hydroxide was added (50 mL, 1M aqueoussolution) and the mixture extracted with methyl-tert-butyl ether. Theorganic phase was stirred with hydrochloric acid (2N, 100 mL) for 4hours. The aqueous layer was then washed with methyl-tert butyl etherbefore being made basic with sodium hydroxide solution (5M) andextracted with dichloromethane/isopropanol (3/1). Evaporation of theorganic layer gave 900 mg of (114) as a yellow oil. R_(t)=1.04 min(Method 10). Detected mass: 224.2 (M+H⁺).

d)1-[3-(7-Chloro-1-methoxyisoquinolin-6-yloxy)-cyclobutyl]-1-(4-fluorophenyl)-propylamine(115 and 116)

1-[3-(7-chloro-1-methoxyisoquinolin-6-yloxy)-cyclobutyl]-1-(4-fluorophenyl)-propylamine(2 isomeric mixtures) were prepared from1-(1-aminopropyl)-1-(4-fluorophenyl)cyclobutan-3-ol (114) and7-chloro-6-fluoro-1-methoxyisoquinoline (10) as described for (109). Thetwo stereoisomers could be separated by silica gel chromatography,relative stereochemistry was not assigned.

115: R_(t)=1.50 min (Method 10). Detected mass: 415.2 (M+H⁺)

116: R_(t)=1.55 min (Method 10). Detected mass: 415.2 (M+H⁺)

e)6-[3-(1-Amino-propyl)-3-(4-fluoro-phenyl)-cyclobutyloxy]-7-chloro-2H-isoquinolin-1-one(Example 125 and 126)

6-[3-(1-Amino-propyl)-3-(4-fluorophenyl)-cyclobutyloxy]-7-chloro-2H-isoquinolin-1-one(Example 125 and 126) were prepared from1-[3-(7-chloro-1-methoxyisoquinolin-6-yloxy)-cyclobutyl]-1-(4-fluorophenyl)-propylamines115 and 116 as described for Example 117.

Example 125: R_(t)=0.94 min (Method 11). Detected mass: 401.1 (M+H⁺).

Example 126: R_(t)=1.34 min (Method 10). Detected mass: 401.1 (M+H⁺).

Example 1276-[3-(1-Amino-propyl)-3-(4-fluoro-phenyl)-cyclopentyloxy]-7-chloro-2H-isoquinolin-1-onea) 1-cyano-1-(4-fluorophenyl)cyclopent-3-ene (117)

Sodium hydride (14.4 g, 0.36 mol, 60% in oil) was added to ice cooledDMSO (500 mL) under argon and stirred for 10 minutes.4-Fluoroacetonitrile (22.4 g, 0.16 mol) was dissolved in DMSO (200 mL)and then added over 15 minutes to the stirred, cooled sodium hydridemixture. After dropwise addition of cis-1,4-dichlorobutene (17.7 g, 14.9mL) the mixture was allowed to warm to room temperature and was thenstirred overnight. The reaction was quenched by gentle addition to 1000mL ice cold water and followed by extraction with dichloromethane.Evaporation gave crude product which was taken up in heptane/ethylacetate (1/1) and washed with water three times. The organic phase wasdried over sodium sulphate, filtered and evaporated to give 33.7 g redoil. This was purified by chromatography on silica gel, elution withheptane/ethyl acetate (1/2) gave 10.1 g of desired compound 117.

b) 1-(1-aminopropyl)-1-(4-fluorophenyl)cyclopent-3-ene (118)

1-cyano-1-(4-fluorophenyl)cyclopent-3-ene (117, 1.4 g, 7.48 mmol) wasdissolved in toluene (3.5 mL) and ethyl magnesium bromide (5 mL, 15mmol, 3M in ether) added. After stirring for 2.5 hours, the reactionmixture was added dropwise to ice cold methanol (50 mL), followed bysodium borohydride (560 mg, 15 mmol). The mixture was warmed to roomtemperature and stirred overnight. The white suspension was treated withsodium hydroxide solution (aq, 1M, 125 mL) and then extracted withdichloromethane/isopropanol (3/1). The organic phase was washed withbrine, dried over sodium sulphate and evaporated to give 1.2 g of ayellow oil. This was taken up in dichloromethane and extracted twicewith dilute hydrochloric acid (2M). The combined aqueous layers weremade basic with aqueous sodium hydroxide solution (5M) and re-extractedwith dichloromethane/isopropanol (3/1). Drying over sodium sulphate andevaporation gave 348 mg of the desired product R_(t)=2.37 min (Method2). Detected mass: 220.1 (M+H⁺).

c) 1-(1-aminopropyl)-1-(4-fluorophenyl)cyclopentan-3-ol (119)

1-(1-aminopropyl)-1-(4-fluorophenyl)cyclopent-3-ene (118, 348 mg, 1.6mmol) was dissolved in THF at 0° C. under argon. Borane (1.75 mL, 1.75mmol, 1M in THF) was added dropwise over 10 minutes. The reactionmixture was allowed to warm to room temperature before stirringovernight. After cooling to 0° C., water was added (4 mL), followed byhydrogen peroxide (0.61 mL, 30% solution in water) and sodium hydroxidesolution (1.75 mL, 1M aqueous solution). After stirring for 5 minutesthe mixture was extracted with ethyl acetate, dried over sodium sulphateand evaporated to give 458 mg of desired product, which was stirred for15 minutes with dilute hydrochloric acid (10 mL, 2M aqueous solution).Evaporation, followed by freeze drying gave 514 mg of the desiredproduct as mixture of four stereoisomers as a colourless hydrochloridesalt. R_(t)=1.83, 1.99, 2.36, 2.86 min (Method 2). Detected mass: 203.1(M—NH₃—H₂O+H⁺).

d)1-[3-(7-chloro-1-methoxyisoquinolin-6-yloxy)-cyclopentyl]-1-(4-fluorophenyl)-propylamine(120)

1-[3-(7-chloro-1-methoxyisoquinolin-6-yloxy)-cyclopentyl]-1-(4-fluorophenyl)-propylamine(120) was prepared from1-(1-aminopropyl)-1-(4-fluorophenyl)cyclopentan-3-ol (119) and7-chloro-6-fluoro-1-methoxyisoquinoline (10) as described for 109.R_(t)=1.11 min (Method 11). Detected mass: 429.3 (M+H⁺). The product wasobtained as a mixture of isomers, their relative stereochemistry was notassigned.

e)6-[3-(1-Amino-propyl)-3-(4-fluorophenyl)-cyclopentyloxy]-7-chloro-2H-isoquinolin-1-one(Example 127)

6-[3-(1-Amino-propyl)-3-(4-fluorophenyl)-cyclopentyloxy]-7-chloro-2H-isoquinolin-1-one(Example 127) was prepared from1-[3-(7-chloro-1-methoxyisoquinolin-6-yloxy)-cyclopentyl]-1-(4-fluorophenyl)-propylamine(120) as described for Example 117. The material was obtained as amixture of stereoisomers, their relative stereochemistry was notassigned. R_(t)=1.34, 1.37 min (Method 10). Detected mass: 415.1 (M+H⁺).

C-(1,4-Dioxa-spiro[4.5]dec-8-yl)-C-(4-methoxy-phenyl)-methylamine (32)

Under argon, 4-methoxy-phenylmagnesium bromide (0.5M in THF, 24 mL, 12mmol) was added to a solution of1,4-dioxa-spiro[4.5]decane-8-carbonitrile (1.0 g, 6 mmol) in THF (100mL). The mixture was stirred under reflux for 16 hours. The reactionmixture was then cooled to 0° C. Saturated sodium sulphate solution wasadded dropwise until no more precipitate formed. The precipitate wasremoved by filtration and washed with THF. The combined organic phaseswere stirred with sodium borohydride (452 mg, 12 mmol) overnight at 25°C. The reaction mixture was then diluted with t-butyl methyl ether (100mL) and treated with 0.05M aqueous hydrochloric acid (three times with100 mL). The combined aqueous phases were adjusted to alkaline pH with a6M aqueous sodium hydroxide solution with cooling, before extractionwith dichloromethane gave a solution of the desired product which wasused directly in the next stage. R_(t)=0.74 min (Method 5). Detectedmass: 278.2 (M+H⁺).

[(4-Methoxy-phenyl)-(4-oxo-cyclohexyl)-methyl]-carbamic acid tert-butylester (33)

With cooling di-tert.-butyl dicarbonate (1.31 g, 6 mmol) andtriethylamine (0.83 mL, 6 mmol) were added to the crude solution ofC-(1,4-dioxa-spiro[4.5]dec-8-yl)-C-(4-methoxy-phenyl)-methylamine (32)from the previous stage. After stirring overnight, the reaction wasworked up by extraction with dichloromethane and washing with 1M HCl.The aqueous layer was treated with 1M NaOH solution to basic pH and thenextracted with dichloromethane. After washing the combined organic phasewith brine, and drying over sodium sulphate, the organic phase wasevaporated to give crude product which was chromatographed on silicagel. Elution with ethyl acetate/hexane (30/70) gave 110 mg of thedesired product. R_(t)=4.42 min (Method 6). Detected mass: 278.1(M-isobutene+H⁺).

[(4-Hydroxy-cyclohexyl)-(4-methoxy-phenyl)-methyl]-carbamic acidtert-butyl ester (34)

Sodium borohydride (12 mg, 0.34 mmol) and 2 drops methanol were added toa solution of [(4-methoxy-phenyl)-(4-oxo-cyclohexyl)-methyl]-carbamicacid tert-butyl ester (33, 110 mg) in THF (5 mL). After stirring for 7hours the reaction was worked up by washing the solution with saturatedsodium bicarbonate solution and brine. After drying the organic phaseover sodium sulphate, followed by filtration, evaporation gave 101 mg ofthe desired cis/trans isomer mixture (34) as a colourless solid, whichwas used directly in the next stage. R_(t)=1.36, 1.39 min (Method 5).Detected mass: 219.2 (M—C₄H₈—CO₂—H₂O⁺).

4-[Amino-(4-methoxy-phenyl)-methyl]-cyclohexanol (35)

Trifluoroacetic acid (0.31 mL) was added to a solution of[(4-hydroxy-cyclohexyl)-(4-methoxy-phenyl)-methyl]-carbamic acidtert-butyl ester (34, 101 mg) in dichloromethane (6 mL). After stirringfor 2 hours, 2M hydrochloric acid (3 mL) was added. Evaporation gavecrude product as a colourless solid. Water and acetonitrile were addedand the mixture was concentrated and then freeze dried to give 83 mg of4-[amino-(4-methoxy-phenyl)-methyl]-cyclohexanol (35) as thehydrochloride salt. R_(t)=0.71 min (Method 5). Detected mass: 219.2(M—NH₂ ⁺).

C-[4-(1-Benzyloxy-7-chloro-isoquinolin-6-yloxy)-cyclohexyl]-C-(4-methoxy-phenyl)-methylamine(36 and 37)

4-[Amino-(4-methoxy-phenyl)-methyl]-cyclohexanol (35, 83 mg, 0.3 mmol)was evaporated twice to dryness from toluene. The residue was dissolvedin dimethylacetamide (1 mL) and the solution added dropwise to asuspension of sodium hydride, (37 mg, 0.92 mmol, 60% in mineral oil) indimethyl acetamide (2 mL) under argon. After stirring for 1 hour asolution of 1-benzyloxy-7-chloro-6-fluoroquinoline (38, 62 mg, 0.21mmol) in dimethylacetamide (2 mL) was then added dropwise and themixture stirred overnight. Then mixture was then treated with water (6mL) to quench the reaction. Product was isolated by extraction withdichloromethane/isopropanol (3:1) and the crude product was thenobtained by evaporation of the organic phase under reduced pressure.Purification by column chromatography (silica gel, 5% methanol indichloromethane) gave 40 mg of the earlier eluting isomer 1 (36) and 40mg of the later eluting isomer 2 (37), both as colourless solids. Therelative stereochemistry was not assigned.

36: R_(t)=1.46 min (Method 5). Detected mass: 503.2 (M+H⁺).

37: R_(t)=1.51 min (Method 5). Detected mass: 503.2 (M+H⁺).

Example 35 and Example 366-{4-[Amino-(4-methoxy-phenyl)-methyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one

A 2M aqueous solution of hydrochloric acid (3.8 mL) was added to asolution ofC-[4-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-cyclohexyl]-C-(4-methoxy-phenyl)-methylamine(36, 40 mg, 0.08 mmol) in isopropanol (4 mL). The reaction mixture wasstirred overnight. Isopropanol was removed under reduced pressure andthe remaining aqueous solution freeze dried to give crude product as anamorphous powder. This was treated twice with acetonitrile/water andfreeze dried to give the desired product as a colourless hydrochloridesalt. The relative stereochemistry was not assigned.

Example 35: R_(t)=2.56 min (Method 1). Detected mass: 396.2 (M—NH₂ ⁺)

Example 36 was synthesized analogously starting from 37: R_(t)=2.86 min(Method 1). Detected mass: 396.2 (M—NH₃+H⁺)

The following four products were obtained by the same proceduredescribed for the synthesis of example 35 and example 36 using1-benzyloxy-7-chloro-6-fluoroisoquinoline and the corresponding4-[amino-phenyl-methyl]-cyclohexanols, using the respective phenylGrignard reagents and 1,4-dioxa-spiro[4.5]decane-8-carbonitriles.

Ex. Iso- R_(t)/ Meth- No. Product Chemical Name [M + H⁺] mer [min] od 37

6-{4-[Amino-(4- fluoro-phenyl)- methyl]-cyclo hexyloxy}-7- chloro-2H-isoquinolin-1- one 401.2 1 2.61 1 38

6-[4-(Amino-p- tolyl-methyl)- cyclohexyloxy]- 7-chloro-2H-isoquinolin-1- one 397.2 1 2.69 1 39

6-[4-(Amino-p- tolyl-methyl)- cyclohexyloxy]- 7-chloro-2H-isoquinolin-1- one 397.0 2 2.63 1 40

6-[4-(Amino- phenyl-methyl)- cyclohexyloxy]- 7-chloro-2H- isoquinolin-1-one 383.2 1 2.51 1

Alternative Synthesis of Example 406-[4-(Amino-phenyl-methyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-onea) 4-Hydroxy-cyclohexanecarbonitrile (121)

A solution of 10.0 g (59.8 mmol) of 4-cyanocyclohexanone cyclic ethyleneacetal in a mixture of 80 mL of acetic acid and 20 mL of water washeated in the microwave oven at 130° C. for 20 min. The mixture wascooled to room temperature and slowly poured onto 2.2 L of coldsaturated aqueous sodium bicarbonate solution. The mixture was extractedtwice with dichloromethane, the organic phase was dried over magnesiumsulphate, filtered, 100 mL of ethanol were added and the dichloromethanewas removed in vacuo. To the solution were then added 2.0 g (52.9 mmol)of sodium borohydride and the mixture was stirred at room temperatureovernight. The reaction mixture was quenched with water, and extractedtwice with dichloromethane. The combined organic layer was concentratedin vacuo to give 6.4 g of 4-hydroxy-cyclohexanecarbonitrile as a mixtureof cis/trans isomers in a purity sufficient for further conversion.R_(t)=0.14 min (Method 18). Detected mass: 126.1 (M+H⁺).

b) 4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexane-carbonitrile (122)

6.4 g (51.1 mmol) of 4-hydroxy-cyclohexanecarbonitrile (121) weredissolved in 120 mL of dichloromethane, cooled to 0° C. and 14.9 mL(13.7 g, 128 mmol) of 2,6-lutidine and 15.4 mL (14.9 g, 56.2 mmol) oftert-butyldimethylsilyltrifluoromethanesulfonate were added. Thereaction mixture was stirred for 16 h at room temperature, thenadditional 5.0 mL of tert-butyldimethylsilyltrifluoromethanesulfonatewere added and stirring continued for 1 h. The reaction mixture wasdiluted with 100 mL of dichloromethane and washed with 100 mL of water,80 mL of saturated aqueous sodium bicarbonate solution and 50 mL ofbrine. The organic phase was dried over magnesium sulphate, filtered,concentrated in vacuo and purified by silica gel chromatography(heptanes:ethyl acetate) to give 9.76 g of the desired product.R_(t)=0.95 min (Method 18). Detected mass: 240.1 (M+H⁺).

c) 4-(Amino-phenyl-methyl)-cyclohexanol (123)

417 mg of 4-(Amino-phenyl-methyl)-cyclohexanol (123) as mixture ofdiastereoisomers was synthesized using the sequence described for thesynthesis of 93, starting from 700 mg of4-(tert-butyl-dimethyl-silanyloxy)-cyclohexanecarbonitrile (122) and2.09 mL (5.85 mmol) of phenylmagnesium bromide. R_(t)=0.43 min (Method18). Detected mass: 206.1 (M+H⁺).

d)6-[4-(amino-phenyl-methyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one(Example 40)

Example 40 was synthesized using the reaction sequence as described forthe synthesis of Example 1. 240 mg of4-(amino-phenyl-methyl)-cyclohexanol (123) and 272 mg of7-chloro-6-fluoro-1-methoxy-isoquinoline (10) were used to give 51 mg ofExample 40 as its hydrochloride. R_(t)=1.34 min (Method 10). Detectedmass: 383.1 (M+H⁺). 28 mg of the other isomer of4-(amino-phenyl-methyl)-cyclohexanol (Example 128) were also isolated asits hydrochloride. R_(t)=1.31 min (Method 10). Detected mass: 383.1(M+H⁺). Separation of the two isomers was accomplished by silica gelchromatography after coupling of aminoalcohol 123 and 10. Relativestereochemistry was not assigned.

The following examples were obtained in a similar fashion as describedfor the alternative preparation of Example 40, using the correspondingisoquinolines and 4-(amino-methyl)-cyclohexanols (prepared following thesequence described for the synthesis of 123) as starting materials:

Ex.- Iso- R_(t)/ Meth No. Product Chemical Name [M + H⁺] mer [min] od129

6-[4-(1-Amino- propyl)-cyclo hexy oxy]-7- chloro-2H-iso quinolin-1-one335.1 1 1.24 10 130

6-[4-(1-Amino- propyl)-cyclo hexyloxy]-7- chloro-2H-iso quinolin-1-one335.1 2 1.19 10 131

6-[4-(Amino- cyclopropyl- methyl)-cyclo hexyloxy]-7- chloro-2H-isoquinolin-1-one 347.2 1 2.38  2 132

6-[4-(Amino- cyclopropyl- methyl)- cyclohexyloxy]- 7-chloro-2H-isoquinolin-1- one 347.2 2 2.36  2

The following racemates were separated by HPLC, using a chiral column.Absolute stereochemistry was not determined, the earlier elutingenantiomer was designated to be enantiomer one. In case of Example 41and Example 42, enantiomeric separation was performed on stage of theracemic O-benzyl protected precursor(1-[trans-4-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-1-phenyl-cyclohexyl]-1-phenyl-methylamine)and the final products were liberated after separation, using thestandard procedure described above. In the case of Example 41 andExample 42, data for retention times is given for said protectedcompounds.

R_(t) chiral Example Racemate Enantiomer Method [min] 41 21 1 B 6.84 4221 2 B 9.01 43 01 1 A 6.18 44 01 2 A 9.22 45 03 1 A 4.98 46 03 2 A 7.0547 26 1 A 6.24 48 26 2 A 8.87 49 24 1 A 4.56 50 24 2 A 7.96 51 37 1 C5.53 52 37 2 C 8.12 53 32 1 A 11.60 54 32 2 A 15.03

The enantiomers obtained from these examples by separation of theracemate are

-   trans-6-[4-((S)-Amino-phenyl-methyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   trans-6-[4-((R)-Amino-phenyl-methyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-((S)-1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-((R)-1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-((S)-Amino-cyclopropyl-methyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-((R)-Amino-cyclopropyl-methyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-((R)-Amino-cyclopropyl-methyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-((S)-Amino-cyclopropyl-methyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-((S)-1-Amino-ethyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-((R)-1-Amino-ethyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,-   6-{4-[(S)-Amino-(4-fluoro-phenyl)-methyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,-   6-{4-[(R)-Amino-(4-fluoro-phenyl)-methyl]cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,-   cis-6-[4-((R)-1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,    and-   cis-6-[4-((S)-1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one.    (enantiomers have not been assigned to “Enantiomer 1” or “Enantiomer    2”, respectively)

LC/MS-Methods: Method 1:

Stationary phase: Waters XBridge C18 Gradient: ACN + 0.05% TFA:H₂O +0.05% TFA 5:95(0 min) to 5:95(0.3 min) to 95:5(3.5 min) to 95:5(4 min)Flow: 1.3 mL/min

Method 2:

Stationary phase: Col YMC Jsphere 33 × 2.1 Gradient: ACN + 0.05%TFA:H₂O + 0.05% TFA 2:98(0 min) to 2:98(1 min) to 95:5(5 min) to95:5(6.25 min) Flow: 1 mL/min

Method 3:

Stationary phase: Waters XBridge C18 Gradient: ACN + 0.1% FA:H₂O + 0.1%FA 3:97(0 min) to 60:40(3.5 min) to 98:2(4.0 min) to 98:2(5.0 min) to3:97(5.2 min) to 3:97(6.5 min) Flow: 1.3 mL/min

Method 4:

Stationary phase: YMCJsphere H80, 33 × 2 Gradient: H₂O + 0.1% FA:ACN +0.08% FA 95:5 (0 min) to 5:95(2.5 min) to 5:95(3 min) Flow: 1.3 mL/min

Method 5

Stationary phase: Col YMC Jsphere ODS H80 20 × 2 Gradient: ACN:H₂O +0.05% TFA 4:96(0 min) to 95:5(2.0 min) to 95:5(2.4 min) Flow: 1 mL/min

Method 6:

Stationary phase: WatersXBridge C18 Gradient: H₂O + 0.1% FA:ACN + 0.08%FA 97:3(0 min) to 40:60(3.5 min) to 2:98(4 min) to 2:98 (5 min) to97:3(5.2 min) to 97:3(6.5 min) Flow: 1.3 mL/min

Method 7:

Stationary phase: Column Acquity BEH C18, 50 × 2.1 mm, 1.7 μm Gradient:H₂O + 0.05% TFA:ACN + 0.035% TFA 98:2(0 min) to 0:100(1.6 min) to0:100(2.1 min) to 98:2(3 min) Flow: 1 mL/min

Method 8:

Stationary phase: Column Gemini C18, 30 × 4.6 mm, 3 μm Gradient: H₂O +0.1% FA:ACN + 0.1% FA 95:5(0 min) to 0:100(5.5 min) to 0:100(7.5 min)Flow: 1 mL/min

Method 9:

Stationary phase: Column Gemini C18, 30 × 4.6 mm, 3 μm Gradient: H₂O +0.1% FA:ACN + 0.1% FA 95:5(0 min) to 95:5(1 min) to 0:100(9 min) to0:100(12 min) Flow: 1 mL/min

Method 10:

Stationary phase: Merck Chromolith fast Grad Gradient: H₂O + 0.05%TFA:ACN + 0.035% TFA 98:2(0 min) to 98:2(0.2 min) to 2:98 (2.4 min) to2:98 (3.2 min) to 98:2(3.3 min) to 98:2(4 min) Flow: 2 mL/min

Method 11:

Stationary phase: Waters Aquity SDS Gradient: H₂O + 0.1% FA:ACN + 0.08%FA 95:5(0 min) to 5:95(1.1 min) to 5:95 (1.7 min) to 95:5 (1.8 min) to95:5(2.0 min) Flow: 0.9 mL/min

Method 12:

Stationary phase: WatersXBridge C18 Gradient: H₂O + 0.05% TFA:ACN +0.05% TFA 95:5(0 min) to 95:5(0.2 min) to 5:95(2.4 min) to 5:95 (3.5min) to 95:5(3.6 min) to 95:5(4.5 min) Flow: 1.7 mL/min

Method 13:

Stationary phase: WatersXBridge C18 Gradient: H₂O + 0.05% TFA:ACN +0.05% TFA 95:5(0 min) to 95:5(0.2 min) to 5:95(2.4 min) to 5:95 (3.2min) to 95:5(3.3 min) to 95:5(4.0 min) Flow: 1.7 mL/min

Method 14:

Stationary phase: WatersXBridge C18 Gradient: H₂O + 0.05% TFA:ACN +0.05% TFA 95:5(0 min) to 95:5(0.1 min) to 5:95(3.3 min) to 95:5(3.85min) to 95:5(4.3 min) Flow: 1.7 mL/min

Method 15:

Stationary phase: Luna 3μ C18(2) 10 × 2.0 mm Gradient: ACN:H₂O + 0.05%TFA 7:93(0 min) to 95:5(1.2 min) to 95:5(1.4 min) Flow: 1.1 mL/min

Method 16:

Stationary phase: Merck Chromolith fast Grad Gradient: H₂O + 0.05%TFA:ACN + 0.05% TFA 98:2(0 min) to 98:2(0.2 min) to 2:98 (2.4 min) to2:98 (3.2 min) to 98:2(3.3 min) to 98:2(4 min) Flow: 2.4 mL/min

Method 17:

Stationary phase: Luna 3μ C18(2) 10 × 2.0 mm (????) Gradient: ACN:H₂O +0.05% TFA 20:80(0 min) to 95:5(0.8 min) to 95:5(1.4 min) to 20:80(1.45min) Flow: 1.1 mL/min

Method 18:

Stationary phase: Luna 3μ C18(2) 10 × 2.0 mm Gradient: ACN:H₂O + 0.05%TFA 7:93(0 min) to 95:5(1.2 min) to 95:5(1.4 min) to 7:93(1.45 min)Flow: 1.1 mL/min

Method 19:

Stationary phase: Col YMC Jsphere ODS H80 20 × 2 Gradient: ACN:H₂O +0.05% TFA 4:96(0 min) to 95:5(2.0 min) to 95:5(2.4 min) to 4:96 (2.45min) Flow: 1 mL/min

Method 20:

Stationary phase: WatersXBridge C18, 4.6, 6 × 50 2.5μ Gradient: Water +0.05% TFA:ACN + 0.05% TFA 95:5(0 min) to 5:95(2.6 min) to 5:95(3.0 min)to 95:5(3.10 min) to 95:5 (4 min) Flow 1.7 mL/min

Method 21:

Stationary phase: WatersXBridge C18, 4.6, 6 × 50 2.5μ Gradient: Water +0.05% TFA:ACN + 0.05% TFA 95:5(0 min) to 95:5(0.2 min) to 5:95(2.4 min)to 5:95(3.5 min) to 95:5(3.6 min) to 95:5(4.5 min) Flow 1.7 mL/min

Methods for Chiral Resolution Method A:

Stationary phase: Chiralpak AD-H, 250 × 4.6 mm Eluent: MeOH:iPrOH 2:1 +0.1% diethylamine Flow: 1 mL/min Detection: 249 nM

Method B:

Stationary phase: Chiralpak AD-H, 250 × 4.6 mm Eluent: Heptane:EtOH:MeOH(5:1:1), column preconditioned with 0.1% diethylamine Flow: 1 mL/minDetection: 249 nM

Method C:

Stationary phase: Chiralpak AD-H, 250 × 4.6 mm. Eluent: MeOH:EtOH(1:1) + 0.1% diethylamine. Flow: 1 mL/min Detection: 249 nM

Determination of Rho Kinase Inhibition

To measure Rho-kinase inhibition, IC₅₀ values were determined accordingto the following protocol:

Active human recombinant ROCK II (N-terminal His6-tagged recombinanthuman ROCK-II residues 11-552) was purchased from Millipore GmbH,Schwalbach, Germany. The peptide substrate,Fluorescein-AKRRRLSSLRA-COOH, was obtained from JPT PeptideTechnologies, Berlin, Germany. Adenosine-5′-triphosphate (ATP), bovineserum albumine (BSA), dimethylsulphoxide (DMSO),4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid (Hepes), Brij-35,dithiothreitol (DTT) and Pluronic F-68 were purchased fromSigma-Aldrich, Munich, Germany. Tris(hydroxymethyl)-aminomethane (Tris),magnesium chloride, NaOH, 1M HCl and EDTA were obtained from MerckBiosciences, Darmstadt, Germany. “Complete” protease inhibitor was fromRoche Diagnostics, Mannheim, Germany.

Test compounds were diluted to the appropriate concentrations in buffer1 (25 mM Tris-HCl, pH 7.4, 5 mM MgCl2, 2 mM DTT, 0.02% (w/v) BSA, 0.01%Pluronic F-68 and 3% DMSO). The ROCK II enzyme was diluted to aconcentration of 100 ng/mL in buffer 2 (25 mM Tris-HCl, pH 7.4, 5 mMMgCl2, 2 mM DTT and 0.02% (w/v) BSA). The peptide substrate and ATP werediluted to concentrations of 3 μM and 120 μM, respectively, in thebuffer 2. Two μl of the compound solution were mixed with 2 μl of thediluted enzyme in a 384-well small volume microtiter plate (Greiner,Bio-One, Frickenhausen, Germany), and the kinase reaction was initiatedby addition of 2 μl of the solution containing peptide substrate andATP. After 60 min incubation at 32° C., the reaction was stopped byaddition of 20 μl of a solution containing 100 mM Hepes-NaOH, pH 7.4,0.015% (v/v) Brij-35, 45 mM EDTA and 0.227% chip coating reagent 1(Caliper Lifescience Inc, Hopkinton, Mass.). Phosphorylation of thesubstrate peptide was then detected on a Caliper 3000 instrumentessentially as described by Pommereau et al (J. Biomol. Screening 9(5),409-416, 2004). Separation conditions were as follows: Pressure −1.3psi, upstream voltage −1562 V, downstream voltage −500 V, sample siptime 200 ms. Positive controls (buffer 1 instead of compound) andnegative controls (buffer 1 instead of compound and buffer 2 instead ofROCK II) were run in parallel on each plate.

The following products/compounds were tested in said assay by using therespective form (salt or free base) obtained as in the examplesdescribed above and the following activities were measured

Example No. pIC50 1 +++++++ 2 +++++++ 3 +++++++ 4 +++++++ 5 +++++++ 6+++++++ 7 +++++++ 8 +++++++ 9 +++++++ 10 +++++++ 11 ++++++ 12 +++++ 13++++++ 14 +++++ 15 +++++++ 16 ++++++ 17 ++++++ 19 +++++ 20 ++++++ 22++++++ 24 +++++++ 25 +++++++ 26 +++++++ 27 ++++++ 28 +++++++ 29 +++++++31 ++++++ 32 ++++++ 34 ++++++ 35 +++++++ 36 ++++++ 37 +++++++ 38 +++++++39 ++++++ 40 +++++ 41 +++++ 42 ++++++ 44 +++++++ 45 +++++++ 46 +++++++51 +++++ 52 +++++++ 53 ++++++ 54 +++++ 55 +++++++ 56 +++++++ 57 +++++++58 +++++++ 59 +++++++ 60 +++++++ 61 +++++ 62 +++++++ 63 +++++++ 64+++++++ 65 +++++ 66 +++++ 67 +++++ 69 +++++++ 70 +++++++ 77 +++++++ 82+++++++ 83 +++++ 84 +++++ 85 +++++ 86 +++++ 87 ++++++ 88 +++++ 89 +++++90 +++++ 92 +++++ 94 +++++ 97 +++++++ 99 +++++++ 100 +++++++ 101 +++++109 ++++++ 110 ++++++ 111 ++++++ 114 +++++++ 115 +++++ 116 ++++++ 117++++++ 118 +++++ 119 +++++ 120 +++++ 121 ++++++ 122 ++++++ 123 ++++++124 ++++++ 125 +++++ 126 +++++ 128 +++++ 129 ++++++ 130 ++++++ 131 +++++

The given activity is denoted as the negative decadal logarithm of theIC₅₀ (pIC₅₀) as follows:

+: pIC50≦3.0++: 3.0≦pIC₅₀<4.0+++: 4.0≦pIC₅₀<5.0++++: 5.0≦pIC₅₀<6.0+++++: 6.0≦pIC50<7.0++++++: 7.0≦pIC50<8.0+++++++: 8.0≦pIC50

Determination of Protein Kinase A and Protein Kinase G Inhibition

To measure PKA and PKG1-beta inhibition, IC₅₀ values were determinedaccording to the following protocol:

Active recombinant human PKG1-beta (full-length, with N-terminalHis-tag) was purchased from Millipore GmbH, Schwalbach, Germany. Activerecombinant human PKA (residues 1-351, N-terminal His-tag) was obtainedfrom Invitrogen, Karlsruhe, Germany. The peptide substrate,Fluorescein-AKRRRLSSLRA-COOH, was obtained from JPT PeptideTechnologies, Berlin, Germany. Adenosine-5′-triphosphate (ATP), bovineserum albumine (BSA), dimethylsulphoxide (DMSO),4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid (Hepes), Brij-35,dithiothreitol (DTT) and Pluronic F-68 were purchased fromSigma-Aldrich, Munich, Germany. Tris(hydroxymethyl)-aminomethane (Tris),magnesium chloride, NaOH, 1M HCl and EDTA were obtained from MerckBiosciences, Darmstadt, Germany. “Complete” protease inhibitor was fromRoche Diagnostics, Mannheim, Germany.

Test compounds were diluted to the appropriate concentrations in buffer1 (25 mM Tris-HCl, pH 7.4, 5 mM MgCl2, 2 mM DTT, 0.02% (w/v) BSA, 0.01%Pluronic F-68 and 3% DMSO). PKG1-beta and PKA were diluted toconcentrations of 150 ng/ml and 30 ng/ml, respectively, in buffer 2. Thepeptide substrate and ATP were diluted to concentrations of 3 μM and 120μM, respectively, in the buffer 2. Two μl of the compound solution weremixed with 2 μl of the diluted enzyme in a 384-well small volumemicrotiter plate (Greiner, Bio-One, Frickenhausen, Germany), and thekinase reaction was initiated by addition of 2 μl of the solutioncontaining peptide substrate and ATP. After 60 min incubation at 32° C.,the reaction was stopped by addition of 20 μl of a solution containing100 mM Hepes-NaOH, pH 7.4, 0.015% (v/v) Brij-35, 45 mM EDTA and 0.227%chip coating reagent 1 (Caliper Lifescience Inc, Hopkinton, Mass.).Phosphorylation of the substrate peptide was then detected on a Caliper3000 instrument essentially as described by Pommereau et al (J. Biomol.Screening 9(5), 409-416, 2004). Separation conditions were as follows:Pressure −1.3 psi, upstream voltage −1562 V, downstream voltage −500 V,sample sip time 200 ms. Positive controls (buffer 1 instead of compound)and negative controls (buffer 1 instead of compound and buffer 2 insteadof kinase solution) were run in parallel on each plate. The followingproducts/compounds were tested in said assay by using the respectiveform (salt or free base) obtained as in the examples described above andthe following activities were measured.

Example No. Selectivity against PKA Selectivity against PKG1 >1000 >1000 2 >1000 >1000 3 >1000 >300 4 >1000 >100 5 >1000 >3006 >1000 >300 7 >1000 >300 8 >1000 >300 9 >1000 >100 10 >100 >10011 >300 >10 12 >100 >10 13 >300 >100 14 >100 >100 15 >1000 >30016 >300 >100 17 >300 >100 19 >100 >100 20 >100 >100 22 >300 >10024 >1000 >300 25 >1000 >100 26 >1000 >300 27 >100 >10 28 >1000 >100029 >1000 >1000 31 >300 >100 32 >1000 >300 34 >300 >10 35 >1000 >10036 >300 >300 37 >1000 >300 38 >1000 >300 39 >100 >100 41 >10 >1042 >300 >300 44 >1000 >1000 45 >1000 >100 46 >1000 >1000 51 >100 >1052 >1000 >300 53 >100 >100 55 >1000 >300 56 >1000 >300 57 >1000 >30058 >1000 >100 59 >1000 >300 60 >1000 >100 61 >10 >1 62 >1000 >30063 >1000 >300 64 >1000 >100 66 >10 >10 69 >1000 >300 70 >1000 >100077 >1000 >300 82 >1000 >1000 83 >100 >10 84 >100 >10 85 >100 >1086 >10 >10 87 >1000 >100 88 >10 >10 97 >1000 >300 99 >1000 >100100 >1000 >1000 109 >300 >100 110 >300 >100 114 >1000 >1000 116 >100 >10117 >300 >10 120 >100 >10 121 >100 >10 122 >300 >10 123 >100 >10124 >100 >10 125 >10 >10 128 >10 >10 129 >100 >10 130 >300 >10131 >10 >10 132 >100 >10

1. A compound of the formula (I)

wherein R₁ is H, OH or NH₂; R₃ is H, halogen, CN, (C₁-C₆)alkyl, OH, NH₂,or NHR′; R₄ is H, halogen, hydroxy, CN, (C₁-C₆)alkyl, R′, or(C₁-C₆)alkylene-R′; R₅ is H, halogen, CN, (C₁-C₆)alkyl, or R′; R₇ is H,halogen, CN, (C₁-C₆)alkyl, O—(C₁-C₆)alkyl, R′, or SO₂—NH₂; R₈ is H,halogen or (C₁-C₆)alkyl; R₉ is R′, OH, halogen, (C₁-C₆)alkyl,O—(C₁-C₆)alkyl, (C₁-C₆)alkylene-R′, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkylene-O—R′, (C₁-C₆)alkylene-CH[R′]₂, (C₁-C₆)alkylene-C(O)—R′,(C₁-C₆)alkylene-C(O)NH₂, (C₁-C₆)alkylene-C(O)NH—R′,(C₁-C₆)alkylene-C(O)NH—(C₁-C₆)alkyl,(C₁-C₆)alkylene-C(O)N[(C₁-C₆)alkyl]₂, (C₁-C₆)alkylene-C(O)N[R′]₂;(C₁-C₆)alkylene-C(O)O—(C₁-C₆)alkyl, COOH, C(O)O—(C₁-C₆)alkyl, C(O)OR′C(O)(C₁-C₆)alkyl, C(O)R′, C(O)NH₂, C(O)—NH—(C₂-C₆)alkenyl,C(O)—NH—(C₂-C₆)alkynyl, C(O)NH—(C₁-C₆)alkyl, C(O)NHR′,C(O)—NH(C₁-C₆)alkylene-R′, C(O)N[(C₁-C₆)alkyl]R′ C(O)N[(C₁-C₆)alkyl]₂,C(O)—(C₁-C₆)alkylene-R′, or C(O)O(C₁-C₆)alkylene-R′; R₆ is absent; or isone (C₁-C₄)alkylene bound to the cycloalkyl ring, in which the(C₁-C₄)alkylene forms a second bond to a different carbon atom of thecycloalkyl ring to form a bicyclic ring system, wherein in the bicyclicring system optionally one or two carbon atomes are replaced by a groupindependently selected from O, N—R₁₅, S, SO or SO₂; or, if m and s are2, m is 3 and s is 1, or m is 4 and s is 0, R₆ is CH₂—CH—(CH₂)₂ which isbound with one CH₂ to the cycloalkyl ring and the two other CH₂ arebound to different carbon atoms of the cycloalkyl ring; and, if m is 3and s is 3, R₆ are two methylene groups bound to different carbon atomsof the cycloalkyl ring, wherein the methylene groups or theCH₂—CH—(CH₂)₂ group are bound to carbon atoms of the cycloaalkyl ringsuch that they form an adamantane system of the formula

wherein L can be bound to any secondary or tertiary carbon atom andwherein the bicyclic ring system or adamantane system is unsubstitutedor optionally substituted by R₉; R₁₀ is H, (C₆-C₁₀)aryl, O—(C₆-C₁₀)aryl,O—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, or (C₅-C₁₀)heteroaryl, wherein(C₆-C₁₀)aryl or (C₅-C₁₀)heteroaryl are unsubstituted or substituted; R₁₁is H, (C₁-C₆)alkyl, (C₁-C₆)alkylene-R′, (C₃-C₈)cycloalkyl,(C₅-C₁₀)heteroaryl, (C₃-C₈)heterocycloalkyl, (C₆-C₁₀)aryl; or R₁₁ andR₁₂ together with carbon atom to which they are attached form a(C₃-C₈)cycloalkyl or a (C₃-C₈)-heterocycloalkyl ring; R₁₂ is(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₁₀)heteroaryl,(C₃-C₈)heterocycloalkyl, or (C₆-C₁₀)aryl; or R₁₂ is H, provided that r=2and the other R₁₂ is not H; or R₁₁ and R₁₂ together with carbon atom towhich they are attached form a (C₃-C₈)cycloalkyl or a(C₃-C₈)-heterocycloalkyl ring; R₁₃ and R₁₄ are independently of eachother H, R′, (C₁-C₆)alkyl, (C₁-C₆)alkylene-R′,(C₁-C₆)alkylene-O—(C₁-C₆)alkyl, (C₁-C₆)alkylene-O—R′,(C₁-C₆)alkylene-CH[R′]₂, (C₁-C₆)alkylene-C(O)—R′,(C₁-C₆)alkylene-C(O)NH₂, (C₁-C₆)alkylene-C(O)NH—R′,(C₁-C₆)alkylene-C(O)NH—(C₁-C₆)alkyl,(C₁-C₆)alkylene-C(O)N[(C₁-C₆)alkyl]₂, (C₁-C₆)alkylene-C(O)N[R′]₂,(C₁-C₆)alkylene-C(O)O—(C₁-C₆)alkyl, C(O)O—(C₁-C₆)alkyl, C(O)OR′,C(O)(C₁-C₆)alkyl, C(O)R′, C(O)NH—(C₁-C₆)alkyl, C(O)NHR′,C(O)N[(C₁-C₆)alkyl]R′ C(O)N[(C₁-C₆)alkyl]₂, C(O)—(C₁-C₆)alkylene-R′,C(O)O(C₁-C₆)alkylene-R′, or R₁₃ and R₁₄, together with the N-atom towhich they are attached, form a (C₃-C₈) heterocycloalkyl; R₁₅ is H or(C₁-C₆)alkyl; n is 0, 1, 2, 3 or 4; m is 1, 2, 3 or 4; s is 0, 1, 2, or3; r is 1 or 2; L is O(CH₂)_(p), S(CH₂)_(p), S(O)(CH₂)_(p),SO₂(CH₂)_(p), NH(CH₂)_(p), N(C₁-C₆)alkyl-(CH₂)_(p),N(C₃-C₆)cycloalkyl-(CH₂)_(p); or N[(C₁-C₃)alkylene-R′]—(CH₂)_(p); p is0, 1, 2, 3 or 4; R′ is (C₃-C₈)cycloalkyl, (C₅-C₁₀)heteroaryl,(C₃-C₈)heterocycloalkyl, (C₆-C₁₀)aryl; wherein in residues R₃ to R₁₅alkyl or alkylene is unsubstituted or optionally substituted one or moretimes by OH, OCH₃, C(O)OH, C(O)OCH₃, NH₂, NHCH₃, N(CH₃)₂, C(O)NH₂,C(O)NHCH₃ or C(O)N(CH₃)₂; wherein in residues R₃ to R₁₅ cycloalkyl orheterocycloalkyl is unsubstituted or optionally substituted one or moretimes by (C₁-C₆)alkyl, halogen, OH, OCH₃, C(O)OH, C(O)OCH₃, NH₂, NHCH₃,N(CH₃)₂, C(O)NH₂, C(O)NHCH₃ or C(O)N(CH₃)₂; wherein in residues R₃ toR₁₅ alkyl or alkylene is unsubstituted or optionally substituted one ormore times by halogen; wherein in residues R₃ to R₁₅ (C₆-C₁₀)aryl and(C₅-C₁₀)heteroaryl are unsubstituted or optionally substituted one ormore times by a group independently selected from halogen, OH, NO₂, N₃,CN, C(O)—(C₁-C₆)alkyl, C(O)—(C₆-C₁₀)aryl, COOH, COO(C₁-C₆)alkyl, CONH₂,CONH(C₁-C₆)alkyl, CON[(C₁-C₆)alkyl]₂, (C₃-C₈)cycloalkyl, (C₁-C₆)alkyl,(C₁-C₆)alkylene-NH(C₁-C₆)alkyl, (C₁-C₆)alkylene-N[(C₁-C₆)alkyl]₂,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, O—(C₁-C₆)alkyl, O—C(O)—(C₁-C₆)alkyl,PO₃H₂, SO₃H, SO₂—NH₂, SO₂NH(C₁-C₆)alkyl, SO₂N[(C₁-C₆)alkyl]₂,S—(C₁-C₆)alkyl; SO—(C₁-C₆)alkyl, SO₂—(C₁-C₆)alkyl,SO₂—N═CH—N[(C₁-C₆)alkyl]₂, SF₅, C(NH)(NH₂), NH₂, NH—(C₁-C₆)alkyl,N[(C₁-C₆)alkyl]₂, NH—C(O)—(C₁-C₆)alkyl, NH—C(O)O—(C₁-C₆)alkyl,NH—SO₂—(C₁-C₆)alkyl, NH—SO₂—(C₆-C₁₀)aryl, NH—SO₂—(C₅-C₁₀)heteroaryl,NH—SO₂—(C₃-C₈)heterocycloalkyl, N(C₁-C₆)alkyl-C(O)—(C₁-C₆)alkyl,N(C₁-C₆)alkyl-C(O)O—(C₁-C₆)alkyl, N(C₁-C₆)alkyl-C(O)—NH—(C₁-C₆)alkyl],(C₆-C₁₀)aryl, (C₁-C₆)alkylene-(C₆-C₁₀)aryl, O—(C₆-C₁₀)aryl,O—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, (C₅-C₁₀)heteroaryl,(C₃-C₈)heterocycloalkyl, (C₁-C₆)alkylene-(C₅-C₁₀)heteroaryl,(C₁-C₆)alkylene-(C₃-C₈)heterocycloalkyl,O—(C₁-C₆)alkylene-(C₅-C₁₀)heteroaryl,O—(C₁-C₆)alkylene-(C₃-C₈)heterocycloalkyl, wherein said (C₆-C₁₀)aryl,(C₅-C₁₀)heteroaryl, (C₃-C₈)heterocycloalkyl or (C₃-C₈)cycloalkyl may besubstituted one to three times by a group independently selected fromhalogen, OH, NO₂, CN, O—(C₁-C₆)alkyl, (C₁-C₆)alkyl, NH₂, NH(C₁-C₆)alkyl,N[(C₁-C₆)alkyl]₂, SO₂CH₃, COOH, C(O)O—(C₁-C₆)alkyl, CONH₂,(C₁-C₆)alkylene-O—(C₁-C₆)alkyl, (C₁-C₆)alkylene-O—(C₆-C₁₀)aryl, orO—(C₁-C₆)alkylene-(C₆-C₁₀)aryl; or wherein (C₆-C₁₀)aryl is vicinallysubstituted by a O—(C₁-C₄)alkylene-O group whereby a 5-8-membered ringis formed together with the carbon atoms the oxygen atoms are attachedto; and wherein aryl substituents of (C₆-C₁₀)aryl, (C₅-C₁₀)heteroaryl,(C₃-C₈)heterocycloalkyl or (C₃-C₈)cycloalkyl groups may not be furthersubstituted by an aryl, heteroaryl, heterocycloalkyl, or(C₃-C₈)cycloalkyl containing group; their stereoisomeric and/ortautomeric forms and/or their pharmaceutically acceptable salts.
 2. Acompound of formula (I) according to claim 1, wherein R₁ is H and ischaracterized by the formula (II)


3. A compound of formula (I) according to claim 1, wherein R₁ is OH andis characterized by the formula (IIIa)

or of the formula (IIIb)


4. A compound according to claim 1, wherein R₁ is NH₂.
 5. A compoundaccording to one of claims 1 to 4, wherein R₃ is H, halogen,(C₁-C₆)alkyl, or NHR′, wherein (C₁-C₆)alkyl and R′ are unsubstituted orsubstituted.
 6. A compound according to one of claims 1 to 5, wherein R₃is H.
 7. A compound according to one of claims 1 to 6, wherein R₄ is H,halogen, (C₁-C₆)alkyl or (C₁-C₂)alkylene-phenyl, wherein (C₁-C₆)alkyl orphenyl are unsubstituted or substituted.
 8. A compound according to oneof claims 1 to 7, wherein R₄ is H or halogen.
 9. A compound according toone of claims 1 to 8, wherein R₅ is H, halogen, (C₁-C₆)alkyl,(C₆-C₁₀)aryl, (C₃-C₈)cycloalkyl or (C₅-C₁₀)heteroaryl, wherein(C₁-C₆)alkyl, (C₆-C₁₀)aryl, (C₃-C₈)cycloalkyl or (C₅-C₁₀)heteroaryl areunsubstituted or substituted.
 10. A compound according to one of claims1 to 9, wherein R₅ is H.
 11. A compound according to one of claims 1 to10, wherein R₇ is H, halogen, (C₁-C₆)alkyl, O—(C₁-C₆)alkyl, or R′,wherein (C₁-C₆)alkyl or R′ are unsubstituted or substituted.
 12. Acompound according to one of claims 1 to 11, wherein R₇ is H, methyl orchloro.
 13. A compound according to one of claims 1 to 12, wherein R₈ isH.
 14. A compound according to one of claims 1 to 13, wherein R₉ is R′OH, halogen, (C₁-C₆)alkyl, (C₁-C₆)alkylene-R′, (C₂-C₆)alkenyl,(C₁-C₆)alkylene-C(O)NH—R′, (C₁-C₆)alkylene-C(O)NH—(C₁-C₆)alkyl, C(O)OH,C(O)NH₂, C(O)NH—(C₁-C₆)alkyl, C(O)NHR′, C(O)—NH—(C₁-C₆)alkynyl,C(O)—NH(C₁-C₆)alkylene-R′, or C(O)N[(C₁-C₈)alkyl]₂; wherein(C₁-C₆)alkyl, (C₁-C₆)alkylene or R′ are unsubstituted or substituted.15. A compound according to one of claims 1 to 14, wherein R₉ is OH,halogen, (C₁-C₆)alkyl, C(O)OH, C(O)NH₂, or O—CH₃, wherein (C₁-C₆)alkylis unsubstituted or substituted.
 16. A compound according to one ofclaims 1 to 15, wherein R₉ is unsubstituted or substituted (C₁-C₆)alkyl.17. A compound according to any of claims 1 to 16, wherein R₁₀ is H,phenyl, O-phenyl, or (C₅-C₆)heteroaryl, wherein phenyl or(C₅-C₆)heteroaryl is unsubstituted or substituted.
 18. A compoundaccording to any of claims 1 to 17, wherein R₁₀ is H or phenyloptionally substituted by (C₁-C₆)alkyl, F, Cl, Br, OMe or CF₃.
 19. Acompound according to any of claims 1 to 18, wherein R₁₀ is H.
 20. Acompound according to any of claims 1 to 19, wherein R₁₁ is H or methyl.21. A compound according to any of claims 1 to 20, wherein R₁₂ is(C₁-C₆)alkyl, wherein optionally one or more hydrogen are substituted byfluoro; (C₃-C₈)cycloalkyl, (C₅-C₆)heteroaryl, or (C₆-C₁₀)aryl, wherein(C₃-C₈)cycloalkyl, (C₅-C₆)heteroaryl or (C₆-C₁₀)aryl are unsubstitutedor substituted.
 22. A compound according to any of claims 1 to 21,wherein R₁₂ is methyl, ethyl, propyl, isopropyl, cyclopropyl,trifluoromethyl, thiazolyl or phenyl unsubstituted or substituted by(C₁-C₄)alkyl or halogen.
 23. A compound according to any of claims 1 to19, wherein R₁₁ and R₁₂ form a substituted or unsubstituted(C₃-C₈)cycloalkyl ring.
 24. A compound according to one of claims 1 to23, wherein R₁₃ and R₁₄ are independently of each other H, R′,(C₁-C₆)alkyl, (C₁-C₆)alkylene-R′, (C₁-C₆)alkylene-O—(C₁-C₆)alkyl,(C₁-C₆)alkylene-O—R′, C(O)(C₁-C₆)alkyl, C(O)R′, or C(O)(C₁-C₆)alkyene-R′C(O)N[(C₁-C₆)alkyl]₂, wherein R′, (C₁-C₆)alkyl, or (C₁-C₆)alkylene areunsubstituted or substituted, or R₁₃ and R₁₄, together with the N-atomto which they are attached, form a unsubstituted or substituted (C₃-C₈)heterocycloalkyl ring.
 25. A compound according to one of claims 1 to24, wherein R₁₃ and R₁₄ are independently of each other H, (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, (C₁-C₄)alkylene-(C₃-C₈)cycloalkyl,(C₁-C₄)alkylene-(C₅-C₁₀)heteroaryl,(C₁-C₄)alkylene-(C₃-C₈)heterocycloalkyl, C₁-C₄)alkylene-(C₆-C₁₀)aryl,(C₁-C₆)alkylene-O—(C₁-C₆)alkyl, C(O)(C₁-C₆)alkyl, or R₁₃ and R₁₄,together with the N-atom to which they are attached, form a (C₃-C₈)heterocycloalkyl group, wherein (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,(C₁-C₄)alkylene, C₅-C₁₀)heteroaryl, (C₃-C₈)heterocycloalkyl, or(C₆-C₁₀)aryl are unsubstituted or substituted.
 26. A compound accordingto any of claims 1 to 25, wherein R₁₃ is H or (C₁-C₆)alkyl; and R₁₄ isH, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₁-C₄)alkylene-(C₃-C₈)cycloalkyl,(C₁-C₄)alkylene-(C₅-C₁₀)heteroaryl,(C₁-C₄)alkylene-(C₃-C₈)heterocycloalkyl, (C₁-C₄)alkylene-(C₆-C₁₀)aryl,or (C₁-C₄)alkylene-O—(C₁-C₆)alkyl, wherein (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, (C₁-C₄)alkylene, (C₅-C₁₀)heteroaryl,(C₃-C₆)heterocycloalkyl, or (C₆-C₁₀)aryl are unsubstituted orsubstituted.
 27. A compound according to any of claims 1 to 26, whereinR₁₃ is H, (C₁-C₆)alkyl and R₁₄ is H, (C₁-C₆)alkyl or (C₃-C₈)cycloalkyl,wherein (C₁-C₆)alkyl or (C₃-C₈)cycloalkyl are unsubstituted orsubstituted.
 28. A compound according to any of claims 1 to 27, whereinR₁₃ and R₁₄ are H.
 29. A compound according to one of claims 1 to 28,wherein R₆ is absent or the bicyclus or adamantane formed with R₆ isselected from

which are unsubstituted or optionally substituted by R₉.
 30. A compoundaccording to one of claims 1 to 29, wherein R₆ is absent.
 31. A compoundaccording to one of claims 1 to 30, wherein m is 2 and s is 2
 32. Acompound according to one of claims 1 to 30, wherein m is 3 and s is 1.33. A compound according to one of claims 1 to 32, wherein n is 0, 1, or2.
 34. A compound according to one of claims 1 to 33, wherein n is 0.35. A compound according to one of claims 1 to 34, wherein r is
 1. 36. Acompound according to one of claims 1 to 35, wherein L is S(CH₂)_(p),S(O)(CH₂)_(p), or SO₂(CH₂)_(p).
 37. A compound according to one ofclaims 1 to 35, wherein L is NH(CH₂)_(p) or N(C₁-C₆)alkyl)-(CH₂)_(p).38. A compound according to one of claims 1 to 35, wherein L isO(CH₂)_(p).
 39. A compound according to one of claims 1 to 38, wherein pis
 0. 40. A compound according to claim 1 selected from the groupconsisting of6-[4-(1-Amino-propyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,6-[4-(1-Amino-cyclopropyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,6-{[4-(1-aminopropyl)-4-phenylcyclohexyl]oxy}-7-chloroisoquinolin-1(2H)-one,6-[4-(1-Amino-butyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,6-[4-(1-Amino-butyl)-4-(4-fluoro-phenyl)-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,6-[4-(1-Amino-propyl)-4-(4-bromo-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,6-[4-(1-Amino-propyl)-4-(2-bromo-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,6-[4-(1-Amino-propyl)-4-(4-trifluoromethyl-phenyl)-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,6-[4-(1-Amino-propyl)-4-(2-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,6-[4-(1-Amino-propyl)-4-(2-chloro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,6-[4-(1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one,6-[4-(1-Amino-ethyl)-4-(4-fluoro-phenyl)-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,6-[4-(1-Amino-2-methyl-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,6-[4-(1-Amino-3-methyl-butyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,6-[4-(Amino-phenyl-methyl)-4-phenyl-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,6-[4-(1-Amino-1-methyl-ethyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,6-[4-(1-Amino-cyclopropyl)-4-(2-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,6-[4-(1-Amino-ethyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,6-[4-(1-Amino-1-methyl-ethyl)-4-phenyl-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,6-(4-[amino(cyclopropyl)methyl]-4-phenyl-cyclohexyl}oxy)-7-chloroisoquinolin-1(2H)-one,6-[4-(1-Amino-propyl)-4-(4-isopropyl-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,6-[4-(1-Amino-propyl)-4-(3-methoxy)-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,6-[4-(1-Amino-propyl)-4-(3-bromo-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,6-[4-(1-Amino-2-methyl-propyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,or6-[4-(1-Amino-propyl)-4-phenyl-cyclohexyloxy]-4-bromo-7-chloro-2H-isoquinolin-1-one,their stereoisomeric and/or tautomeric forms and/or theirpharmaceutically acceptable salts thereof.
 41. A compound according toclaim 1 selected from the group consisting ofcis-6-[4-(1-Amino-propyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,trans-6-[4-(1-amino-propyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-on,cis-6-[4-(1-Amino-cyclopropyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-{[4-(1-Amino-propyl)-4-phenylcyclohexyl]oxy}-7-chloro-2H-isoquinolin-1-one,trans-6-[4-(1-Amino-propyl)-4-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-butyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,trans-6-[4-(1-Amino-butyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-butyl)-4-(4-fluoro-phenyl)-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,trans-6-[4-(1-Amino-butyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amin-propyl)-4-(4-bromo-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(2-bromo-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(4-trifluoromethyl-phenyl)-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(2-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(2-chloro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-ethyl)-4-(4-fluoro-phenyl)-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,trans-6-[4-(1-Amino-ethyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(3-bromo-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,trans-6-[4-(1-Amino-propyl)-4-(3-bromo-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(3-methoxy)-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,trans-6-[4-(1-Amino-propyl)-4-(3-methoxy-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,trans-6-[4-(Amino-phenyl-methyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,trans-6-[4-(1-Amino-2-methyl-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,trans-6-[4-(1-Amino-3-methyl-butyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,trans-6-[4-(Amino-phenyl-methyl)-4-phenyl-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,trans-6-[4-(1-Amino-1-methyl-ethyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-cyclopropyl)-4-(2-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-ethyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-1-methyl-ethyl)-4-phenyl-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-(4-[amino(cyclopropyl)methyl]-4-phenyl-cyclo-hexyl}oxy)-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(4-isopropyl-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-2-methyl-propyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,andcis-6-[4-(1-Amino-propyl)-4-phenyl-cyclohexyloxy]-4-bromo-7-chloro-2H-isoquinolin-1-one,their stereoisomeric and/or tautomeric forms and/or pharmaceuticallyacceptable salts thereof.
 42. A compound according to claim 1 selectedfrom the group consisting oftrans-6-[4-((S)-Amino-phenyl-methyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,trans-6-[4-((R)-Amino-phenyl-methyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-((S)-1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-((R)-1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-((S)-Amino-cyclopropyl-methyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-((R)-Amino-cyclopropyl-methyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-((R)-Amino-cyclopropyl-methyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-((S)-Amino-cyclopropyl-methyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-((S)-1-Amino-ethyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-((R)-1-Amino-ethyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,6-{4-[(S)-Amino-(4-fluoro-phenyl)-methyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,6-{4-[(R)-Amino-(4-fluoro-phenyl)-methyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,cis-6-[4-((R)-1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,andcis-6-[4-((S)-1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,their tautomeric forms and/or pharmaceutically acceptable salts thereof.43. A compound according to claim 1 selected from the group consistingofcis-6-[4-(1-Amino-propyl)-4-pyridin-2-yl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(2,4-difluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(4-fluoro-2-methyl-phenyl)cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(3,5-difluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(3,4-difluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-o-tolyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(2-trifluoromethoxy-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(4-fluoro-3-methoxy-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(3-ethoxy-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(3-methoxy-4-methyl-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(3,4-difluoro-phenyl)-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(3,5-difluoro-phenyl)-cyclohexyloxy]-7-fluoro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(3,4-difluoro-phenyl)-cyclohexyloxy]-7-fluoro-5-methyl-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(3,5-difluoro-phenyl)-cyclohexyloxy]-7-methoxy-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(2-methoxy-phenyl)-cyclohexyloxy]-7-chloro-2Hisoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(4-trifluoro-methoxy-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-1-methyl-ethyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(3,5-difluoro-phenyl)-cyclohexyloxy]-4-benzyl-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(3,5-difluoro-phenyl)-cyclohexyloxy]-5-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(3,5-difluoro-phenyl)-cyclohexyloxy]-5,7-dimethyl-2H-isoquinolin-1-one,cis-6-[4-(Amino-cyclopropyl-methyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(3-trifluoromethyl-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(3-trifluoromethoxy-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(3-trifluoromethoxy-phenyl)-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-(3-trifluoromethyl-phenyl)-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-fluoro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-fluoro-5-methyl-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-propyl)-4-phenyl-cyclohexyloxy]-4-benzyl-7-chloro-2H-isoquinolin-1-one,cis-4-[1-(1-Amino-propyl)-4-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-cyclohexyl]-benzonitrile,cis-3-[1-(1-Amino-propyl)-4-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-cyclohexyl]-benzonitrile,6-[cis-4-(1-Amino-propyl)-4-(3-methanesulfonyl-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,6-[(1S,4S,5S)-5-(1-Amino-propyl)-5-phenyl-bicyclo[2.2.1]hept-2-yloxy]-7-chloro-2H-isoquinolin-1-one,6-[(1R,4R,5R)-5-(1-Amino-propyl)-5-phenyl-bicyclo[2.2.1]hept-2-yloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Benzylamino-propyl)-4-phenyl-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one,cis-6-[4-(1-Diethylamino-propyl)-4-phenyl-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one,cis-7-Methyl-6-[4-(1-propylamino-propyl)-4-(3-trifluoromethyl-phenyl)-cyclohexyloxy]-2H-isoquinolin-1-one,cis-6-[4-(1-Benzylamino-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-7-Chloro-6-[4-(1-isobutylamino-propyl)-4-phenyl-cyclohexyloxy]-2H-isoquinolin-1-one,cis-6-[4-(1-Butylamino-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-7-Chloro-6-{4-[1-(cyclopropylmethyl-amino)-propyl]-4-phenyl-cyclohexyloxy}-2H-isoquinolin-1-one,cis-6-[4-(2-Amino-propyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(2-Amino-butyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-2-fluoro-ethyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,cis-6-[4-(1-Amino-3-methoxy-propyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,6-[3-(1-Amino-propyl)-3-(4-fluoro-phenyl)-cyclobutyloxy]-7-chloro-2H-isoquinolin-1-one,and6-[3-(1-Amino-propyl)-3-(4-fluoro-phenyl)-cyclopentyloxy]-7-chloro-2H-isoquinolin-1-one,and their stereoisomeric and/or tautomeric forms and/or theirpharmaceutically acceptable salts thereof.
 44. A compound according toclaim 1 is selected from the group consisting ofcis-1-[4-(7-Chloro-isoquinolin-6-yloxy)-1-(3,4-difluoro-phenyl)-cyclohexyl]-propylamine,cis-1-[4-(7-Bromo-isoquinolin-6-yloxy)-1-(3,4-difluoro-phenyl)-cyclohexyl]-propylamine,cis-1-[1-(3,5-Difluoro-phenyl)-4-(5,7-dimethyl-isoquinolin-6-yloxy)-cyclohexyl]-propylamine,cis-1-[1-(3,5-Difluoro-phenyl)-4-(7-fluoro-5-methyl-isoquinolin-6-yloxy)-cyclohexyl]-propylamine,cis-1-[1-(3,4-Difluoro-phenyl)-4-(7-fluoro-isoquinolin-6-yloxy)-cyclohexyl]-propylamine,cis-1-[4-(7-Chloro-isoquinolin-6-yloxy)-1-(3,5-difluoro-phenyl)-cyclohexyl]-propylamine,cis-1-[4-(5-Chloro-isoquinolin-6-yloxy)-1-(3,5-difluoro-phenyl)-cyclohexyl]-propylamine,cis-1-[4-(7-Chloro-isoquinolin-6-yloxy)-1-phenyl-cyclohexyl]-propylamine,cis-1-[4-(5,7-Dimethyl-isoquinolin-6-yloxy)-1-phenyl-cyclohexyl]-propylamine,cis-1-[4-(7-Fluoro-isoquinolin-6-yloxy)-1-phenyl-cyclohexyl]-propylamine,cis-1-[4-(5-Chloro-isoquinolin-6-yloxy)-1-phenyl-cyclohexyl]-propylamine,cis-1-[4-(7-Fluoro-5-methyl-isoquinolin-6-yloxy)-1-phenyl-cyclohexyl]-propylamine,cis-1-[4-(7-Bromo-isoquinolin-6-yloxy)-1-phenyl-cyclohexyl]-propylamine,cis-1-[4-(7-Methyl-isoquinolin-6-yloxy)-1-phenyl-cyclohexyl]-propylamine,cis-6-[4-(1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-isoquinolin-1-ylamine,[4-(1-Amino-propyl)-4-(4-methoxy-phenyl)-cyclohexyl]-isoquinolin-6-yl-amine,and1-Amino-[4-(1-amino-propyl)-4-(4-methoxy-phenyl)-cyclohexyl]-isoquinolin-6-yl-amine,and their stereoisomeric and/or tautomeric forms and/or theirpharmaceutically acceptable salts thereof.
 45. A compound according toclaim 1 selected from the group consisting of6-[4-(1-Amino-1-phenyl-ethyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,6-{4-[Amino-(4-methoxy-phenyl)-methyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,6-{4-[Amino-(4-fluoro-phenyl)-methyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,6-[4-(Amino-p-tolyl-methyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,or6-[4-(Amino-phenyl-methyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,and their stereoisomeric and/or tautomeric forms and/or theirpharmaceutically acceptable salts thereof.
 46. A compound according toclaim 1 is selected from the group consisting of6-{4-[1-Amino-1-(4-fluoro-phenyl)-ethyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,6-{4-[1-Amino-1-(4-methoxy-phenyl)-ethyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,6-{4-[1-Amino-1-cyclopentyl-ethyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,6-{4-[1-Amino-1-ethyl-propyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,6-{4-[1-Amino-1-cyclopropyl-ethyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,6-{4-[1-Amino-1-n-propyl-ethyl]cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,6-[4-(1-Amino-propyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, and6-[4-(Amino-cyclopropyl-methyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,and their stereoisomeric and/or tautomeric forms and/or theirpharmaceutically acceptable salts thereof.
 47. A compound of formula (I)and/or its pharmaceutically acceptable salt according to one of claims 1to 46 for use as a medicament.
 48. Use of at least one compound offormula (I) and/or a pharmaceutically acceptable salt thereof accordingto one of claims 1 to 46 for producing a medicament.
 49. Use of at leastone compound of formula (I) and/or a pharmaceutically acceptable saltthereof according to one of claims 1 to 46 for the treatment and/orprevention of hypertension, pulmonary hypertension, ocular hypertension,retinopathy, glaucoma, peripheral circulatory disorder, peripheralarterial occlusive disease (PAOD), coronary heart disease, anginapectoris, heart hypertrophy, heart failure, ischemic diseases, ischemicorgan failure (end organ damage), fibroid lung, fibroid liver, liverfailure, nephropathy, renal failure, fibroid kidney, renalglomerulosclerosis, organ hypertrophy, asthma, chronic obstructivepulmonary disease (COPD), adult respiratory distress syndrome,thrombotic disorders, stroke, cerebral vasospasm, cerebral ischemia,pain, neuronal degeneration, spinal cord injury, Alzheimer's disease,premature birth, erectile dysfunction, endocrine dysfunctions,arteriosclerosis, prostatic hypertrophy, diabetes and complications ofdiabetes, metabolic syndrome, blood vessel restenosis, atherosclerosis,inflammation, autoimmune diseases, AIDS, osteopathy, infection ofdigestive tracts with bacteria, sepsis or cancer development andprogression.
 50. Use of a compound of formula (I) and/or apharmaceutically acceptable salt thereof according to one of claims 1 to46 for the treatment and/or prevention of hypertension, pulmonaryhypertension, fibroid liver, liver failure, nephropathy, renal failure,chronic obstructive pulmonary disease (COPD), cerebral vasospasm, pain,spinal cord injury, erectile dysfunction, blood vessel restenosis, orcancer development and progression.
 51. Use of a compound of formula (I)and/or a pharmaceutically acceptable salt thereof according to one ofclaims 1 to 46 for curative approaches associated with stem cell orinduced pluripotent stem cell treatment, improvement of recognition orfor treatment or prevention of depression, epilepsy, fibroid heart,renal papillary necrosis, tubulo-interstitial dysfunction, multiplesclerosis, vessel stenosis or lipid disorders.
 52. A medicamentcomprising an effective amount of at least one compound of formula (I)and/or a pharmacologically acceptable salt thereof according to one ofclaims 1 to 46, pharmaceutically tolerated excipients and carriers and,where appropriate, further additives and/or other active ingredients.